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Raqib R, Sarker P. Repurposed Drugs and Plant-Derived Natural Products as Potential Host-Directed Therapeutic Candidates for Tuberculosis. Biomolecules 2024; 14:1497. [PMID: 39766204 PMCID: PMC11673177 DOI: 10.3390/biom14121497] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2024] [Revised: 11/15/2024] [Accepted: 11/22/2024] [Indexed: 01/11/2025] Open
Abstract
Tuberculosis (TB) is one of the leading causes of death due to infectious disease. It is a treatable disease; however, conventional treatment requires a lengthy treatment regimen with severe side effects, resulting in poor compliance among TB patients. Intermittent drug use, the non-compliance of patients, and prescription errors, among other factors, have led to the emergence of multidrug-resistant TB, while the mismanagement of multidrug-resistant TB (MDR-TB) has eventually led to the development of extensively drug-resistant tuberculosis (XDR-TB). Thus, there is an urgent need for new drug development, but due to the enormous expenses and time required (up to 20 years) for new drug research and development, new therapeutic approaches to TB are required. Host-directed therapies (HDT) could be a most attractive strategy, as they target the host defense processes instead of the microbe and thereby may prevent the alarming rise of MDR- and XDR-TB. This paper reviews the progress in HDT for the treatment of TB using repurposed drugs which have been investigated in clinical trials (completed or ongoing) and plant-derived natural products that are in clinical or preclinical trial stages. Additionally, this review describes the existing challenges to the development and future research directions in the implementation of HDT.
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Affiliation(s)
- Rubhana Raqib
- Immunobiology, Nutrition and Toxicology Unit, Nutrition Research Division, International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b), Dhaka 1212, Bangladesh;
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Lewis JH, Korkmaz SY, Rizk CA, Copeland MJ. Diagnosis, prevention and risk-management of drug-induced liver injury due to medications used to treat mycobacterium tuberculosis. Expert Opin Drug Saf 2024; 23:1093-1107. [PMID: 39212296 DOI: 10.1080/14740338.2024.2399074] [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: 04/16/2024] [Revised: 07/19/2024] [Accepted: 08/22/2024] [Indexed: 09/04/2024]
Abstract
INTRODUCTION Many of the first line medications for the treatment of active and latent M. tuberculosis are hepatoxic and cause a spectrum of anti-tuberculosis drug induced liver injury (ATLI), including acute liver failure (ALF). Despite advances in recognition of and prevention of ATLI, isoniazid remains one of the leading causes of DILI as well as drug-induced ALF. AREAS COVERED A literature search of the incidence, risk factors, current societal guidelines, monitoring, and prophylactic medication usage in ATLI was performed using PubMed and institutional websites. Relevant articles from 1972 to 2024 were included in this review. EXPERT OPINION Current societal guidelines regarding ATLI monitoring are mixed, but many recommend liver enzyme testing of high-risk populations. We recommend liver test monitoring for all patients on multi-drug therapy as well as those on isoniazid therapy. Precision medicine practices, such as N-acetyltransferase-2 polymorphism genotyping, are thought to be beneficial in reducing the incidence of ATLI in high-risk populations. However, broader implementation is currently cost prohibitive. Hepatoprotective drugs are not currently recommended, although we do recognize their potential. In patients who develop ATLI but require ongoing anti-TB treatment, strategies to restart the same or less hepatotoxic regimens are currently being followed.
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Affiliation(s)
- James H Lewis
- Department of Medicine, Division of Gastroenterology-Hepatology, Medstar Georgetown University Hospital, Washington, DC, USA
| | - Serena Y Korkmaz
- Department of Medicine, General Internal Medicine, Medstar Georgetown University Hospital, Washington, DC, USA
| | - Courtney A Rizk
- Department of Medicine, General Internal Medicine, Medstar Georgetown University Hospital, Washington, DC, USA
| | - Matthew J Copeland
- Department of Medicine, Division of Infectious Diseases, Washington, DC, USA
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Jaffar HM, Al‐Asmari F, Khan FA, Rahim MA, Zongo E. Silymarin: Unveiling its pharmacological spectrum and therapeutic potential in liver diseases-A comprehensive narrative review. Food Sci Nutr 2024; 12:3097-3111. [PMID: 38726410 PMCID: PMC11077231 DOI: 10.1002/fsn3.4010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2023] [Revised: 01/18/2024] [Accepted: 01/24/2024] [Indexed: 05/12/2024] Open
Abstract
Liver diseases, encompassing conditions such as cirrhosis, present a substantial global health challenge with diverse etiologies, including viral infections, alcohol consumption, and non-alcoholic fatty liver disease (NAFLD). The exploration of natural compounds as therapeutic agents has gained traction, notably the herbal remedy milk thistle (Silybum marianum), with its active extract, silymarin, demonstrating remarkable antioxidant and hepatoprotective properties in extensive preclinical investigations. It can protect healthy liver cells or those that have not yet sustained permanent damage by reducing oxidative stress and mitigating cytotoxicity. Silymarin, a natural compound with antioxidant properties, anti-inflammatory effects, and antifibrotic activity, has shown potential in treating liver damage caused by alcohol, NAFLD, drug-induced toxicity, and viral hepatitis. Legalon® is a top-rated medication with excellent oral bioavailability, effective absorption, and therapeutic effectiveness. Its active component, silymarin, has antioxidant and hepatoprotective properties, Eurosil 85® also, a commercial product, has lipophilic properties enhanced by special formulation processes. Silymarin, during clinical trials, shows potential improvements in liver function, reduced mortality rates, and alleviation of symptoms across various liver disorders, with safety assessments showing low adverse effects. Overall, silymarin emerges as a promising natural compound with multifaceted hepatoprotective properties and therapeutic potential in liver diseases.
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Affiliation(s)
- Hafiza Madiha Jaffar
- University Institute of Diet & Nutritional Sciences, Faculty of Allied Health SciencesThe University of LahoreLahorePakistan
| | - Fahad Al‐Asmari
- Department of Food and Nutrition Sciences, College of Agricultural and Food SciencesKing Faisal UniversityAl‐AhsaSaudi Arabia
| | - Faima Atta Khan
- University Institute of Diet & Nutritional Sciences, Faculty of Allied Health SciencesThe University of LahoreLahorePakistan
- Department of Food Science, Faculty of Life SciencesGovernment College UniversityFaisalabadPakistan
| | - Muhammad Abdul Rahim
- Department of Food Science, Faculty of Life SciencesGovernment College UniversityFaisalabadPakistan
- Department of Food Science & Nutrition, Faculty of Medicine and Allied Health SciencesTimes InstituteMultanPakistan
| | - Eliasse Zongo
- Laboratoire de Recherche et d'Enseignement en Santé et Biotechnologies AnimalesUniversité Nazi BONIBobo DioulassoBurkina Faso
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Mohammadi S, Ashtary-Larky D, Asbaghi O, Farrokhi V, Jadidi Y, Mofidi F, Mohammadian M, Afrisham R. Effects of silymarin supplementation on liver and kidney functions: A systematic review and dose-response meta-analysis. Phytother Res 2024; 38:2572-2593. [PMID: 38475999 DOI: 10.1002/ptr.8173] [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: 03/29/2023] [Revised: 01/12/2024] [Accepted: 02/11/2024] [Indexed: 03/14/2024]
Abstract
It is suggested that supplementation with silymarin (SIL) has beneficial impacts on kidney and liver functions. This systematic review and dose-response meta-analysis assessed the impact of SIL administration on certain hepatic, renal, and oxidative stress markers. A systematic search was conducted in various databases to identify relevant trials published until January 2023. Randomized controlled trials (RCTs) that evaluated the effects of SIL on kidney and liver markers were included. A random-effects model was used for the analysis and 41 RCTs were included. The pooled results indicated that SIL supplementation led to a significant reduction in serum levels of alkaline phosphatase, alanine transaminase, creatinine, and aspartate aminotransferase, along with a substantial elevation in serum glutathione in the SIL-treated group compared to their untreated counterparts. In addition, there was a nonsignificant decrease in serum levels of gamma-glutamyl transferase, malondialdehyde (MDA), total bilirubin, albumin (Alb), total antioxidant capacity, and blood urea nitrogen. Sub-group analyses revealed a considerable decline in MDA and Alb serum values among SIL-treated participants with liver disease in trials with a longer duration (≥12 weeks). These findings suggest that SIL may ameliorate certain liver markers with potential hepatoprotective effects, specifically with long-term and high-dose supplementation. However, its nephroprotective effects and impact on oxidative stress markers were not observed. Additional high-quality RCTs with longer durations are required to determine the clinical efficacy of SIL supplementation on renal and oxidative stress markers.
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Affiliation(s)
- Shooka Mohammadi
- Department of Social and Preventive Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Damoon Ashtary-Larky
- Nutrition and Metabolic Diseases Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Omid Asbaghi
- Cancer Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Vida Farrokhi
- Department of Hematology, Faculty of Allied Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Yasaman Jadidi
- Department of Clinical Laboratory Sciences, Faculty of Allied Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Mofidi
- Department of Clinical Nutrition and Dietetics, National Nutrition and Food Technology Research Institute, Faculty of Nutrition and Food Technology, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mehrnaz Mohammadian
- Department of Exercise Physiology, Islamic Azad University of Ahvaz, Ahvaz, Iran
| | - Reza Afrisham
- Department of Clinical Laboratory Sciences, Faculty of Allied Medicine, Tehran University of Medical Sciences, Tehran, Iran
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Bahari H, Shahraki Jazinaki M, Rashidmayvan M, Taheri S, Amini MR, Malekahmadi M. The effects of silymarin consumption on inflammation and oxidative stress in adults: a systematic review and meta-analysis. Inflammopharmacology 2024; 32:949-963. [PMID: 38372848 DOI: 10.1007/s10787-023-01423-6] [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: 09/23/2023] [Accepted: 12/24/2023] [Indexed: 02/20/2024]
Abstract
BACKGROUND Owing to the rich phytochemical content of Silymarin, it may effectively manage inflammation and oxidative stress. We, therefore, aimed to examine the existing evidence on the effect of Silymarin consumption on inflammation and oxidative stress factors by conducting a systematic review and meta-analysis of randomized controlled trials. METHODS A systematic literature search up to September 2023 was completed in PubMed/Medline, Scopus, and Web of Science, to identify eligible RCTs. Heterogeneity tests of the selected trials were performed using the I2 statistic. Random effects models were assessed based on the heterogeneity tests, and pooled data were determined as weighted mean differences with a 95% confidence interval. RESULTS Fifteen RCTs were included in this meta-analysis. Our findings showed that Silymarin consumption significantly decreased CRP (WMD, - 0.50 mg/L; 95% CI, (- 0.95 to - 0.04); p = 0.03), MDA (WMD, - 1.19 nmol/mL; 95% CI, (- 1.99 to - 0.38); p = 0.004), and IL-6 (WMD, - 0.44 pg/ml; 95% CI, (- 0.75 to - 0.12); p = 0.006). Silymarin consumption had no significant effects on IL-10, TAC, and GSH. A significant non-linear relationship was observed between the duration of the intervention and MDA changes. CONCLUSIONS Silymarin can help reduce inflammation in patients with diabetes and thalassemia by reducing MDA as an oxidative stress marker and CRP and IL-6 as inflammatory markers.
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Affiliation(s)
- Hossein Bahari
- Transplant Research Center, Clinical Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mostafa Shahraki Jazinaki
- Department of Nutrition, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad Rashidmayvan
- Department of Nutrition, Food Sciences and Clinical Biochemistry, School of Medicine, Social Determinants of Health Research Center, Gonabad University of Medical Science, Gonabad, Iran
| | - Shaghayegh Taheri
- Department of Clinical Biochemistry, School of Medicine, Birjand University of Medical Sciences, Birjand, Iran
| | - Mohammad Reza Amini
- Student Research Committee, Department of Clinical Nutrition and Dietetics, Faculty of Nutrition Sciences and Food Technology, National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Nutrition and Food Security Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mahsa Malekahmadi
- Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran.
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Alene KA, Hertzog L, Gilmour B, Clements ACA, Murray MB. Interventions to prevent post-tuberculosis sequelae: a systematic review and meta-analysis. EClinicalMedicine 2024; 70:102511. [PMID: 38434448 PMCID: PMC10907188 DOI: 10.1016/j.eclinm.2024.102511] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Revised: 02/07/2024] [Accepted: 02/16/2024] [Indexed: 03/05/2024] Open
Abstract
Background Tuberculosis (TB) remains a global public health challenge, causing substantial mortality and morbidity. While TB treatment has made significant progress, it often leaves survivors with post-TB sequelae, resulting in long-term health issues. Current healthcare systems and guidelines lack comprehensive strategies to address post-TB sequelae, primarily due to insufficient evidence. This systematic review and meta-analysis aimed to identify effective interventions for preventing post-TB sequelae. Methods A systematic search was conducted across four databases including PubMed, SCOPUS, Web of Science, and Cochrane Central Register of Controlled Trials from inception to September 22, 2023. Eligible studies reported interventions designed to prevent post-TB sequelae were included. A random effect meta-analysis was conducted where applicable, and heterogeneity between studies was evaluated visually using forest plots and quantitatively using an index of heterogeneity (I2). This study is registered with PROSPERO (CRD42023464392). Findings From the 2525 unique records screened, 25 studies involving 10,592 participants were included. Different interventions were evaluated for different outcomes. However, only a few interventions were effective in preventing post-TB sequelae. Rehabilitation programs significantly improved lung function (Hedges's g = 0.21; 95% confidence interval (CI): 0.03, 0.39) and prevented neurological sequelae (relative risk (RR) = 0.10; 95% CI: 0.02, 0.42). Comprehensive interventions and cognitive-behavioural therapy significantly reduced the risk of mental health disorders among TB survivors (Hedges's g = -1.89; 95% CI: -3.77, -0.01). In contrast, interventions targeting post-TB liver sequelae, such as vitamin A and vitamin D supplementation and hepatoprotective agents, did not show significant reductions in sequelae (RR = 0.90; 95% CI: 0.52, 1.57). Moreover, adjunctive therapies did not show a significant effect in preventing post-TB neurological sequelae (RR = 0.62, 95% CI: 0.31, 1.24). Interpretation Rehabilitation programs prevented post-TB lung, neurologic and mental health sequelae, while adjuvant therapies and other interventions require further investigation. Funding Healy Medical Research Raine Foundation, Curtin School of Population Health and the Australian National Health and Medical Research Council.
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Affiliation(s)
- Kefyalew Addis Alene
- School of Population Health, Faculty of Health Sciences, Curtin University, Australia
- Geospatial and Tuberculosis Research Team, Telethon Kids Institute, Australia
- Department of Global Health and Social Medicine, Harvard Medical School, Boston, MA, USA
| | - Lucas Hertzog
- School of Population Health, Faculty of Health Sciences, Curtin University, Australia
| | - Beth Gilmour
- School of Population Health, Faculty of Health Sciences, Curtin University, Australia
- Geospatial and Tuberculosis Research Team, Telethon Kids Institute, Australia
| | | | - Megan B Murray
- Department of Global Health and Social Medicine, Harvard Medical School, Boston, MA, USA
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Carty J, Navarro VJ. Dietary Supplement-Induced Hepatotoxicity: A Clinical Perspective. J Diet Suppl 2024; 22:58-77. [PMID: 38528750 DOI: 10.1080/19390211.2024.2327546] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/27/2024]
Abstract
The consumption of dietary supplements (DS) has resulted in a significant and escalating number of cases involving liver injury. It is crucial for clinicians and consumers to be well informed about the adverse effects of such products, leading to their discontinuation and timely reporting of any harmful cases. This article delves into the clinical perspective of DS-related hepatotoxicity, highlighting key concepts such as a systematic diagnostic approach. The discussion extends to notable examples of both currently popular and potential future dietary supplements, such as garcinia cambogia, turmeric, and ashwagandha, accompanied by an overview of recent findings. Causality assessment tools play a crucial role in establishing a connection between these products and instances of liver injury, with consideration of the advantages and disadvantages associated with their use. Fostering a comprehensive understanding of regulatory standards, coupled with a solid foundation of knowledge of DS, will prove instrumental in preventing DS-related hepatotoxicity. Achieving this goal requires collaborative efforts from both consumers and clinicians.
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Affiliation(s)
- Jordan Carty
- Department of Medicine, Jefferson Einstein Medical Center, Philadelphia, PA, USA
| | - Victor J Navarro
- Department of Medicine, Jefferson Einstein Medical Center, Philadelphia, PA, USA
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Mancak M, Altintas D, Balaban Y, Caliskan UK. Evidence-based herbal treatments in liver diseases. HEPATOLOGY FORUM 2024; 5:50-60. [PMID: 38283267 PMCID: PMC10809338 DOI: 10.14744/hf.2022.2022.0052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Revised: 01/09/2024] [Accepted: 01/12/2024] [Indexed: 01/30/2024]
Abstract
The liver is the main organ for metabolic and detoxification reactions in the body. Therefore, its diseases can be associated with both metabolic disorders, such as insulin resistance, obesity, diabetes, or dyslipidemia, and exogenous insults such as drugs, xenobiotics, or alcohol. Indeed, lifestyle changes are the primary approaches for the prevention and treatment of liver diseases. Since ancient times, herbals have also been used for preventive and therapeutic purposes, because of their anti-apoptotic, anti-inflammatory, and antioxidant effects. Here, the literature was reviewed for potential therapeutic effects of plants and their compounds by including in vitro and in vivo studies, as well as clinical trials. Although the available data imply some beneficial roles of herbals on the liver, the indications and posology of specific plants need to be clarified through multicenter, randomized clinical trials.
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Affiliation(s)
- Methiye Mancak
- Department of Pharmacognosy and Pharmaceutical Botany, Gazi University Faculty of Pharmacy, Ankara, Turkiye
| | - Dudu Altintas
- Department of Pharmacognosy, Duzce University Faculty of Pharmacy, Duzce, Turkiye
| | - Yasemin Balaban
- Division of Gastroenterology, Department of Internal Medical Sciences, Hacettepe University School of Medicine, Ankara, Turkiye
| | - Ufuk Koca Caliskan
- Department of Pharmacognosy and Pharmaceutical Botany, Gazi University Faculty of Pharmacy, Ankara, Turkiye
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Singh D, Khan MA, Siddique HR. Unveiling the therapeutic promise of natural products in alleviating drug-induced liver injury: Present advancements and future prospects. Phytother Res 2024; 38:22-41. [PMID: 37775996 DOI: 10.1002/ptr.8022] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Revised: 09/10/2023] [Accepted: 09/15/2023] [Indexed: 10/01/2023]
Abstract
Drug-induced liver injury (DILI) refers to adverse reactions to small chemical compounds, biological agents, and medical products. These reactions can manifest as acute or chronic damage to the liver. From 1997 to 2016, eight drugs, including troglitazone, nefazodone, and lumiracoxib, were removed from the market due to their liver-damaging effects, which can cause diseases. We aimed to review the recent research on natural products and their bioactive components as hepatoprotective agents in mitigating DILI. Recent articles were fetched via searching the PubMed, PMC, Google Scholar, and Web of Science electronic databases from 2010 to January 2023 using relevant keywords such as "natural products," "acetaminophen," "antibiotics," "paracetamol," "DILI," "hepatoprotective," "drug-induced liver injury," "liver failure," and "mitigation." The studies reveal that the antituberculosis drug (acetaminophen) is the most frequent cause of DILI, and natural products have been largely explored in alleviating acetaminophen-induced liver injury. They exert significant hepatoprotective effects by preventing mitochondrial dysfunction and inflammation, inhibiting oxidative/nitrative stress, and macromolecular damage. Due to the bioavailability and dietary nature, using natural products alone or as an adjuvant with existing drugs is promising. To advance DILI management, it is crucial to conduct well-designed randomized clinical trials to evaluate natural products' efficacy and develop new molecules clinically. However, natural products are a promising solution for remedying drug-induced hepatotoxicity and lowering the risk of DILI.
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Affiliation(s)
- Deepti Singh
- Molecular Cancer Genetics and Translational Research Lab, Section of Genetics, Department of Zoology, Aligarh Muslim University, Aligarh, India
| | - Mohammad Afsar Khan
- Molecular Cancer Genetics and Translational Research Lab, Section of Genetics, Department of Zoology, Aligarh Muslim University, Aligarh, India
| | - Hifzur R Siddique
- Molecular Cancer Genetics and Translational Research Lab, Section of Genetics, Department of Zoology, Aligarh Muslim University, Aligarh, India
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Akkahadsee P, Sawangjit R, Phumart P, Chaiyakunapruk N, Sakloetsakun D. Systematic review and network meta-analysis of efficacy and safety of interventions for preventing anti-tuberculosis drug induced liver injury. Sci Rep 2023; 13:19880. [PMID: 37963954 PMCID: PMC10645982 DOI: 10.1038/s41598-023-46565-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Accepted: 11/02/2023] [Indexed: 11/16/2023] Open
Abstract
Anti-tuberculosis drug induced liver injury (Anti-TB DILI) is the most common adverse events (AEs) necessitating therapy interruption but there is no preventing regimen. This study aimed to examine the efficacy and safety of herbs/alternative medicines for preventing anti-TB DILI. Relevant articles were identified through a systematic search in 5 international databases from inception till March 2022. All randomized controlled trials (RCT) assessing the effects of herbal or alternative medicines against anti-TB DILI were included. The network meta-analysis (NMA) was used to synthesize the evidence for preventing hepatotoxicity using a random-effects model. A total of 3423 patients from 14 RCTs were included. The NMA indicated that supplementation of Turmeric plus Tinospora cordifolia (RR 0.07; 95% CI 0.02 to 0.28), and N-acetyl cysteine (NAC) (RR 0.09; 95% CI 0.01 to 0.75) significantly reduced the incidence of anti-TB DILI compared with placebo. In addition, poly herbal product significantly reduced alkaline phosphatase (ALP) (MD - 21.80; 95% CI - 33.80 to - 9.80) and total bilirubin (Tbil) compared with placebo (MD - 0.51; 95% CI - 0.76 to - 0.26). There was no statistically significant difference in the occurrence of AEs in any intervention. In conclusion, Turmeric plus Tinospora cordifolia, NAC and poly-herbal product may provide benefit for preventing anti-TB DILI in TB patients. However, these findings are based on a small number of studies. Additional studies are warranted to confirm the findings.
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Affiliation(s)
- Pattaraporn Akkahadsee
- Master Degree of Clinical Pharmacy, Faculty of Pharmacy, Mahasarakham University, MahaSarakham, Thailand
| | - Ratree Sawangjit
- Clinical Trials and Evidence-Based Syntheses Research Unit (CTEBs RU), Mahasarakham University, MahaSarakham, Thailand.
| | - Panumart Phumart
- Department of Social and Administrative Pharmacy, Faculty of Pharmaceutical Sciences, Khon Kaen University, Khon Kaen, Thailand
| | - Nathorn Chaiyakunapruk
- Department of Pharmacotherapy, College of Pharmacy, University of Utah, Salt Lake City, UT, USA
- IDEAS Center, Veterans Affairs Salt Lake City Healthcare System, Salt Lake City, UT, USA
| | - Duangkamon Sakloetsakun
- Department of Pharmaceutical Technology, Faculty of Pharmaceutical Sciences, Khon Kaen University, Khon Kaen, Thailand
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Liu Y, Wu M, Ren M, Bao H, Wang Q, Wang N, Sun S, Xu J, Yang X, Zhao X, Bao Y, He G, Xu W. From Medical Herb to Functional Food: Development of a Fermented Milk Containing Silybin and Protein from Milk Thistle. Foods 2023; 12:foods12061308. [PMID: 36981234 PMCID: PMC10048290 DOI: 10.3390/foods12061308] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Accepted: 03/09/2023] [Indexed: 03/30/2023] Open
Abstract
Milk thistle is a traditional medicinal herb. Silybin is a medicinal component found in the seed coat of milk thistle, which has liver-protective and anti-cancer properties. Conventional studies have focused on the extraction of silybin with organic reagents, which was inapplicable to the food industry. This study aims to develop a fermented milk containing silybin and protein from the milk thistle seeds. A three step procedure was developed, comprising homogenization of milk thistle seeds, NaHCO3 heat treatment, and microbial fermentation. The silybin was characterized by high performance liquid chromatography, and the protein was quantified and electrophorized. It was found that the homogenization step was essential for the preparation of protein, and the NaHCO3 heat treatment was the crucial step in obtaining silybin. The optimal NaHCO3 treatment settings were 1% NaHCO3, 60°C, and 3 h, and the optimal strains for microbial fermentation were L131 (Rummeliibacillus stabekisii) and RS72 (Lactobacillus plantarum). The silybin yield in the fermented milk reached 11.24-12.14 mg/g seeds, accounting for 72.6-78.4% of the total silybin in the milk thistle seeds, and the protein yield reached 121.8-129.6 mg/g seeds. The fermented milk had a slightly sweet yoghurt-like flavor and could be used as a dietary supplement for silybin and protein.
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Affiliation(s)
- Yanxia Liu
- School of Ocean Science and Technology, Panjin Institute of Industrial Technology, Dalian University of Technology, Panjin Campus, Panjin 124221, China
| | - Minghuo Wu
- School of Ocean Science and Technology, Panjin Institute of Industrial Technology, Dalian University of Technology, Panjin Campus, Panjin 124221, China
| | - Miaomiao Ren
- School of Ocean Science and Technology, Panjin Institute of Industrial Technology, Dalian University of Technology, Panjin Campus, Panjin 124221, China
| | - Haijun Bao
- Yingkou Chenguang Extraction Equipment Co., Ltd., Yingkou 115000, China
| | - Qing'an Wang
- Yingkou Chenguang Extraction Equipment Co., Ltd., Yingkou 115000, China
| | - Nan Wang
- Yingkou Chenguang Extraction Equipment Co., Ltd., Yingkou 115000, China
| | - Shibo Sun
- School of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin Campus, Panjin 124221, China
| | - Jianqiang Xu
- School of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin Campus, Panjin 124221, China
| | - Xiaojing Yang
- School of Ocean Science and Technology, Panjin Institute of Industrial Technology, Dalian University of Technology, Panjin Campus, Panjin 124221, China
| | - Xu Zhao
- School of Ocean Science and Technology, Panjin Institute of Industrial Technology, Dalian University of Technology, Panjin Campus, Panjin 124221, China
| | - Yongming Bao
- School of Ocean Science and Technology, Panjin Institute of Industrial Technology, Dalian University of Technology, Panjin Campus, Panjin 124221, China
| | - Gaohong He
- State Key Laboratory of Fine Chemicals, School of Chemical Engineering, Dalian University of Technology, Dalian 116024, China
| | - Weiping Xu
- School of Ocean Science and Technology, Panjin Institute of Industrial Technology, Dalian University of Technology, Panjin Campus, Panjin 124221, China
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Aghemo A, Alekseeva OP, Angelico F, Bakulin IG, Bakulina NV, Bordin D, Bueverov AO, Drapkina OM, Gillessen A, Kagarmanova EM, Korochanskaya NV, Kucheryavii UA, Lazebnik LB, Livzan MA, Maev IV, Martynov AI, Osipenko MF, Sas EI, Starodubova A, Uspensky YP, Vinnitskaya EV, Yakovenko EP, Yakovlev AA. Role of silymarin as antioxidant in clinical management of chronic liver diseases: a narrative review. Ann Med 2022; 54:1548-1560. [PMID: 35635048 PMCID: PMC9186366 DOI: 10.1080/07853890.2022.2069854] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Chronic liver disease (CLD), manifested as hepatic injury, is a major cause of global morbidity and mortality. CLD progresses to fibrosis, cirrhosis, and-ultimately-hepatocellular carcinoma (HCC) if left untreated. The different phenotypes of CLD based on their respective clinical features and causative agents include alcoholic liver disease (ALD), non-alcoholic fatty liver disease (NAFLD), metabolic-associated fatty liver disease (MAFLD), and drug-induced liver injury (DILI). The preferred treatment modality for CLD includes lifestyle modification and diet, along with limited pharmacological agents for symptomatic treatment. Moreover, oxidative stress (OS) is an important pathological mechanism underlying all CLD phenotypes; hence, the use of antioxidants to manage the disease is justified. Based on available clinical evidence, silymarin can be utilized as a hepatoprotective agent, given its potent antioxidant, antifibrotic, and anti-inflammatory properties. The role of silymarin in suppressing OS has been well established, and therefore silymarin is recommended for use in ALD and NAFLD in the guidelines approved by the Russian Medical Scientific Society of Therapists and the Gastroenterology Scientific Society of Russia. However, to discuss the positioning of the original silymarin in clinical guidelines and treatment protocols as a hepatoprotective agent for managing CLD concomitantly with other therapies, an expert panel of international and Russian medical professionals was convened on 11 November 2020. The panel reviewed approaches for the prevention and treatment of OS, existing guidelines for patient management for CLD, and available evidence on the effectiveness of silymarin in reducing OS, fibrosis, and hepatic inflammation and presented in the form of a narrative review. Key messagesAn expert panel of international and Russian medical professionals reviewed existing guidelines for ALD, NAFLD, MAFLD, and DILI to establish consensus recommendations that oxidative stress is the common pathophysiological mechanism underlying these conditions.The panel also discussed the positioning of original silymarin in clinical guidelines and treatment protocols as a hepatoprotective agent for managing CLD concomitantly with other therapies.The panel reviewed the effectiveness of 140 mg original silymarin three times a day in reducing oxidative stress in chronic liver diseases such as ALD, NAFLD, MAFLD, and DILI.
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Affiliation(s)
- Alessio Aghemo
- Department of Biomedical Sciences, Humanitas Research Hospital IRCCS, Sosnowiec, Poland
| | - Olga P Alekseeva
- Gastroenterological Center, Semashko National Research University, Moscow, Russia
| | | | - Igor G Bakulin
- Department of Propaedeutics of Internal Diseases, Federal State Medical University of Ministry of Health of Russia, Chief Specialist-Therapist of the North-Western Federal district, Moscow, Russia
| | - Natalia V Bakulina
- Department of Therapy and Clinical Pharmacology, North-Western State Medical University, Moscow, Russia
| | - Dmitry Bordin
- Department of Pancreatic, Biliary, and Upper Digestive Tract Disorders, A.S. Loginov Moscow Clinical Scientific Center, Moscow, Russia
| | - Alexey O Bueverov
- Department of Gastroenterology and Hepatology, Moscow Medical Academy, Moscow, Russia
| | - Oxana M Drapkina
- Ministry of Health of the Russian Federation, Chief Specialist of Therapy and General Practice Ministry of Health of Russia, Grozny, Russia
| | - Anton Gillessen
- Department of Internal Medicine, Herz-Jesu-Hospital, Muenster, Germany
| | - Elvira M Kagarmanova
- Gastroenterological Department, GBUZ RB City clinical Hospital, Sterlitamak, Russia
| | | | - U A Kucheryavii
- Department of Propaedeutics of Internal Diseases and Gastroenterology, Moscow State University of Medicine and Dentistry, Moscow, Russia
| | - Leonid B Lazebnik
- Department of Polyclinic Therapy, Moscow State University of Medicine and Dentistry, Moscow, Russia
| | - Maria A Livzan
- Department of Faculty Therapy, Omsk State Medical University, Omsk, Russia
| | - Igor V Maev
- Department of Propedeutics of Internal Diseases and Gastroenterology, Moscow State University of Medicine and Dentistry, Moscow, Russia
| | - Anatolii I Martynov
- Department of Internal Diseases, Moscow State University of Medicine and Dentistry, Moscow, Russia
| | - Marina F Osipenko
- Department for Science, Innovations and Informatization, Novosibirsk State Medical University, Novosibirsk, Russia
| | - Evgenii I Sas
- 2nd Department of Therapy, Ministry of Defense of the Russian Federation, Moscow, Russia
| | - Antonina Starodubova
- Department of Scientific and Clinical Work, INSTITUTE "Federal Research Center of Nutrition and Biotechnologies", Moscow, Russia
| | - Yurii P Uspensky
- Department of faculty therapy, Saint Petersburg State Pediatric Medical University (Spbpgmu) of the RF MOH, St. Petersburg, Russia
| | - Elena V Vinnitskaya
- Department of Hepatology, Moscow Clinical Research and Practice Center, Moscow, Russia
| | - Emilia P Yakovenko
- Department of Gastroenterology, Faculty of Advanced Medical Education of the Russian National Research Medical University, Moscow, Russia
| | - Alexey A Yakovlev
- Department of gastroenterology and endoscopy, Rostov State Medical, Rostov, Russia
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Mechanistic Insights into the Pharmacological Significance of Silymarin. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27165327. [PMID: 36014565 PMCID: PMC9414257 DOI: 10.3390/molecules27165327] [Citation(s) in RCA: 58] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Revised: 08/17/2022] [Accepted: 08/18/2022] [Indexed: 12/29/2022]
Abstract
Medicinal plants are considered the reservoir of diverse therapeutic agents and have been traditionally employed worldwide to heal various ailments for several decades. Silymarin is a plant-derived mixture of polyphenolic flavonoids originating from the fruits and akenes of Silybum marianum and contains three flavonolignans, silibinins (silybins), silychristin and silydianin, along with taxifolin. Silybins are the major constituents in silymarin with almost 70–80% abundance and are accountable for most of the observed therapeutic activity. Silymarin has also been acknowledged from the ancient period and is utilized in European and Asian systems of traditional medicine for treating various liver disorders. The contemporary literature reveals that silymarin is employed significantly as a neuroprotective, hepatoprotective, cardioprotective, antioxidant, anti-cancer, anti-diabetic, anti-viral, anti-hypertensive, immunomodulator, anti-inflammatory, photoprotective and detoxification agent by targeting various cellular and molecular pathways, including MAPK, mTOR, β-catenin and Akt, different receptors and growth factors, as well as inhibiting numerous enzymes and the gene expression of several apoptotic proteins and inflammatory cytokines. Therefore, the current review aims to recapitulate and update the existing knowledge regarding the pharmacological potential of silymarin as evidenced by vast cellular, animal, and clinical studies, with a particular emphasis on its mechanisms of action.
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Gillessen A, Angelico F, Chen J, Lu L, Lucena MI, Fu Q, Xie Q, Andrade RJ, Xie W, Xu X, Yu Y, Mao YM, Nan Y. Silymarin for Treating Toxic Liver Disease: International Consensus Recommendations. GASTRO HEP ADVANCES 2022; 1:882-893. [PMID: 39131840 PMCID: PMC11307908 DOI: 10.1016/j.gastha.2022.05.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Accepted: 05/09/2022] [Indexed: 08/13/2024]
Abstract
Chronic liver disease (CLD) is a leading health problem impacting the quality of life globally. China shares a major global burden of CLD-including alcoholic liver disease, nonalcoholic fatty liver disease/metabolic dysfunction-associated fatty liver disease, and drug-induced liver injury, except for chronic viral hepatitis. Several exogenous toxins or endogenous metabolic insults trigger hepatic pathology toward steatosis, inflammation, and fibrosis, which, if left untreated, may culminate in liver cirrhosis. Oxidative stress is a common pathomechanism underlying all phenotypes of toxic liver injury; thus, these may be brought under a unified entity, viz. toxic liver disease (TLD). Therefore, a common strategy to treat TLD is to use antioxidants as hepatoprotective agents. The cornerstone for treating fatty liver disease is lifestyle modification, diet, exercise, and behavioral therapy, along with the limited use of pharmacological agents. Available preclinical and clinical evidence indicates that silymarin is a hepatoprotective agent with established antioxidant, anti-inflammatory, antifibrotic effects. An international expert panel of clinicians was convened to discuss combining alcoholic liver disease, nonalcoholic fatty liver disease/metabolic dysfunction-associated fatty liver disease, drug-induced liver injury, and liver cirrhosis under the single definition of TLD, based on the shared pathologic mechanism of oxidative stress. The panel highlighted the significance of silymarin as an antioxidant treatment for TLD.
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Affiliation(s)
- Anton Gillessen
- Department of Internal Medicine, Herz-Jesu-Hospital, Muenster, Germany
| | - Francesco Angelico
- Department of Public Health and Infectious Diseases, Sapienza University School of Medicine, Rome, Italy
| | - Jun Chen
- Department of Liver Disease Medical Center/Head of the Fourth Department of Liver Disease, Shenzhen Third People's Hospital, Shenzhen, China
| | - Lungen Lu
- Department of Gastroenterology, Shanghai General Hospital, Shanghai, China
| | - Maria Isabel Lucena
- Department of Pharmacology, School of Medicine, University of Málaga, Málaga, Spain
| | - Qingchun Fu
- Department of Liver Disease, Centre of Shanghai Public Health Clinical Centre, Shanghai, China
| | - Qing Xie
- Department of Infectious Diseases, Ruijin Hospital, Shanghai, China
| | - Raul J. Andrade
- Services of Gastroenterology & Clinical Pharmacology, Málaga Biomedical Research Institute, IBIMA, University Hospital, University of Málaga, Málaga, Spain
| | - Wen Xie
- Liver Disease Centre, Beijing Ditan Hospital Capital Medical University, Beijing, China
| | - Xiaoyuan Xu
- Department of Infectious Diseases, Peking University Health Science Centre, Beijing, China
| | - Yanyan Yu
- Department of Infectious Disease, Peking University First Hospital, Beijing, China
| | - Yi-min Mao
- Department of Gastroenterology, Renji Hospital, Shanghai, China
| | - Yuemin Nan
- Department of Liver Diseases, The Third Hospital of Hebei Medical University, Shijiazhuang, China
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Yang Z, Tong C, Qian X, Wang H, Wang Y. Mechanical Bowel Preparation Is a Risk Factor for Postoperative Delirium as It Alters the Gut Microbiota Composition: A Prospective Randomized Single-Center Study. Front Aging Neurosci 2022; 14:847610. [PMID: 35444528 PMCID: PMC9014128 DOI: 10.3389/fnagi.2022.847610] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Accepted: 02/18/2022] [Indexed: 12/12/2022] Open
Abstract
Background and Objective Postoperative delirium (POD) is a frequent complication in patients undergoing gastrectomy. Increasing evidence suggests that abnormal gut microbiota composition may contribute to its morbidity. However, it is unclear whether mechanical bowel preparation would cause postoperative delirium by altering the gut microbiota of patients. This study aimed to investigate the association between mechanical bowel preparation and postoperative delirium in patients undergoing gastrectomy. Methods A prospective randomized single-center study was performed. A total of 81 patients with gastric cancer were enrolled and randomly assigned to two groups: preparation group and non-preparation group according to whether the patient received MBP before surgery. To diagnose postoperative delirium, we used the 3-Min Diagnostic Interview for Confusion Assessment Method-defined delirium for five successive days after surgery. 16s rRNA gene sequencing was used to investigate changes in the intestinal bacteria. The linear discriminant analysis and effect size (LefSe) analysis were also used to identify the different taxa of fecal microbiota between the postoperative delirium and non-postoperative delirium groups. Results We found that there was a significant difference in β-diversity of the gut microbiota between the preparation group and non-preparation group (P = 0.048). Furthermore, patients in the preparation group had a much higher rate of postoperative delirium (13/40, 32.5%) compared with that in non-preparation groups (4/41, 9.8%). Multivariate regression analysis adjusted by other risk factors indicated that mechanical bowel preparation was associated with the occurrence of delirium (odds ratio = 4.792; 95% confidence interval: 1.274–18.028; P = 0.020). When comparing the gut microbiota of patients with and without POD, Bacteroides and Veillonella (genus), which were higher in the preparation group, were also higher in delirium patients (P < 0.05). Genus Olsenella was both relatively higher in the non-preparation group and non-POD group (P < 0.05). Conclusion Mechanical bowel preparation not only altered the gut microbiota composition of patients with gastric cancer but also increased the incidence of postoperative delirium. Among all the gut microbiota altered by mechanical bowel preparation, Bacteroides and Veillonella genus might be a risk factor of POD. Genus Olsenella might be a beneficial bacteria to reduce the incidence of POD.
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Maddahi SZ, Jokar A, Kamalinejad M, Behnampur N. The efficacy of Jujube syrup on the prevention of drug-induced hepatotoxicity in pulmonary tuberculosis patients: A pilot randomized double-blind placebo-controlled clinical trial. Pharmacol Res Perspect 2021; 10:e00902. [PMID: 34939363 PMCID: PMC8929366 DOI: 10.1002/prp2.902] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Accepted: 11/05/2021] [Indexed: 11/12/2022] Open
Abstract
Liver injury is the most common complication of anti-tuberculosis drugs that can cause significant problems. The study aimed to determine the effectiveness of Jujube syrup on the prevention of antituberculosis drug-induced hepatotoxicity (DIH). This pilot randomized double-blind study was conducted based on a placebo-controlled design in patients with tuberculosis (TB). The patients were divided into two groups based on the block random allocation method and received 10 cc of jujube or placebo syrup per day. The liver enzyme levels were assessed as primary outcomes, and the severity of cough, anorexia, and nausea along with the quality of life (QOL) was assessed as secondary outcomes. Finally, eight and nine patients in the jujube and placebo groups completed the study, respectively. In the second week of the study, 27.3% of the patients in the placebo group developed hepatotoxicity. Moreover, there was no liver toxicity in the jujube group. This difference between the two groups was statistically significant (p = .037). Furthermore, the severity of cough in patients in the jujube group decreased significantly during weeks 2 and 4. The QOL significantly improved in the jujube group, compared to the placebo group. This study suggested that Jujube syrup could prevent anti-TB DIH. It can also improve the severity of cough and the QOL in pulmonary TB patients.
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Affiliation(s)
- Seyedeh Zahra Maddahi
- Persian Medicine, Student Research Committee, Mazandaran University of Medical Sciences, Sari, Iran.,Antimicrobial Resistance Research Center, Mazandaran University of Medical Sciences, Sari, Iran
| | - Assie Jokar
- Faculty of Medicine, Department of Persian Medicine, Mazandaran University of Medical Sciences, Sari, Iran.,Traditional and Complementary Medicine Research Center, Addiction Institute, Mazandaran University of Medical Sciences, Sari, Iran
| | - Mohammad Kamalinejad
- School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Nasser Behnampur
- Department of Biostatistics, Health Management and Social Development Research Center, Golestan University of Medical Sciences, Gorgan, Iran
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Zhou Y, Wang J, Zhang D, Liu J, Wu Q, Chen J, Tan P, Xing B, Han Y, Zhang P, Xiao X, Pei J. Mechanism of drug-induced liver injury and hepatoprotective effects of natural drugs. Chin Med 2021; 16:135. [PMID: 34895294 PMCID: PMC8665608 DOI: 10.1186/s13020-021-00543-x] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Accepted: 11/21/2021] [Indexed: 02/06/2023] Open
Abstract
Drug-induced liver injury (DILI) is a common adverse drug reaction (ADR) and a serious threat to health that affects disease treatments. At present, no targeted clinical drugs are available for DILI. Traditional natural medicines have been widely used as health products. Some natural medicines exert specific hepatoprotective effects, with few side effects and significant clinical efficacy. Thus, natural medicines may be a promising direction for DILI treatment. In this review, we summarize the current knowledge, common drugs and mechanisms of DILI, as well as the clinical trials of natural drugs and their bioactive components in anticipation of the future development of potential hepatoprotective drugs.
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Affiliation(s)
- Yongfeng Zhou
- College of Pharmacy, Chengdu University of Traditional Chinese Medicine, 1166 Liutai Avenue, Wenjiang District, Chengdu, 611137 Sichuan China
- Department of Pharmacy, Medical Supplies Center of PLA General Hospital, 100#, West 4th Ring Middle Rd., Fengtai, Beijing, 10039 China
| | - Junnan Wang
- School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing, 102488 China
- Department of Pharmacy, Medical Supplies Center of PLA General Hospital, 100#, West 4th Ring Middle Rd., Fengtai, Beijing, 10039 China
| | - Dingkun Zhang
- College of Pharmacy, Chengdu University of Traditional Chinese Medicine, 1166 Liutai Avenue, Wenjiang District, Chengdu, 611137 Sichuan China
| | - Jiaxin Liu
- Department of Pharmacy, Medical Supplies Center of PLA General Hospital, 100#, West 4th Ring Middle Rd., Fengtai, Beijing, 10039 China
| | - Qinghua Wu
- College of Pharmacy, Chengdu University of Traditional Chinese Medicine, 1166 Liutai Avenue, Wenjiang District, Chengdu, 611137 Sichuan China
| | - Jiang Chen
- College of Pharmacy, Chengdu University of Traditional Chinese Medicine, 1166 Liutai Avenue, Wenjiang District, Chengdu, 611137 Sichuan China
| | - Peng Tan
- College of Pharmacy, Chengdu University of Traditional Chinese Medicine, 1166 Liutai Avenue, Wenjiang District, Chengdu, 611137 Sichuan China
| | - Boyu Xing
- Department of Pharmacy, Medical Supplies Center of PLA General Hospital, 100#, West 4th Ring Middle Rd., Fengtai, Beijing, 10039 China
| | - Yanzhong Han
- College of Pharmacy, Chengdu University of Traditional Chinese Medicine, 1166 Liutai Avenue, Wenjiang District, Chengdu, 611137 Sichuan China
- Department of Pharmacy, Medical Supplies Center of PLA General Hospital, 100#, West 4th Ring Middle Rd., Fengtai, Beijing, 10039 China
| | - Ping Zhang
- Department of Pharmacy, Medical Supplies Center of PLA General Hospital, 100#, West 4th Ring Middle Rd., Fengtai, Beijing, 10039 China
| | - Xiaohe Xiao
- Department of Liver Disease, Fifth Medical Center of PLA General Hospital, 100#, West 4th Ring Middle Rd., Fengtai, Beijing, 10039 China
| | - Jin Pei
- College of Pharmacy, Chengdu University of Traditional Chinese Medicine, 1166 Liutai Avenue, Wenjiang District, Chengdu, 611137 Sichuan China
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Fatima S, Kumari A, Dwivedi VP. Advances in adjunct therapy against tuberculosis: Deciphering the emerging role of phytochemicals. MedComm (Beijing) 2021; 2:494-513. [PMID: 34977867 PMCID: PMC8706769 DOI: 10.1002/mco2.82] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Revised: 04/08/2021] [Accepted: 04/13/2021] [Indexed: 12/14/2022] Open
Abstract
Eastern countries are a major source of medicinal plants, which set up a rich source of ethnopharmacologically known medicines used in the treatment of various diseases. These traditional medicines have been known as complementary, alternative, or nonconventional therapy across globe for ages. Tuberculosis (TB) poses a huge global burden and leads to maximum number of deaths due to an infectious agent. Treatment of TB using Directly Observed Treatment Short-course (DOTS) therapy comprises multiple antibiotics is quite lengthy and causes serious side-effects in different organs. The length of the TB treatment leads to withdrawal from the patients, which paves the way for the emergence of drug resistance in the bacterial population. These concerns related to therapy need serious and immediate interventions. Traditional medicines using phytochemicals has shown to provide tremendous potential in TB treatment, mainly in the eradication of Mycobacterium tuberculosis (M.tb), increasing natural immunity, and managing the side effects of anti-TB drugs. This review describes the antituberculosis potential of selected ethnopharmacologically important phytochemicals as potential immune-modulator and as an adjunct-therapy in TB. This review will be a useful reference for researchers working on ethnopharmacology and will open the door for the discovery of novel agents as an adjunct-therapy to tuberculosis.
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Affiliation(s)
- Samreen Fatima
- Immunobiology GroupInternational Centre for Genetic Engineering and BiotechnologyNew DelhiIndia
| | - Anjna Kumari
- Immunobiology GroupInternational Centre for Genetic Engineering and BiotechnologyNew DelhiIndia
| | - Ved Prakash Dwivedi
- Immunobiology GroupInternational Centre for Genetic Engineering and BiotechnologyNew DelhiIndia
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Islam A, Mishra A, Siddiqui MA, Siddiquie S. Recapitulation of Evidence of Phytochemical, Pharmacokinetic and Biomedical Application of Silybin. Drug Res (Stuttg) 2021; 71:489-503. [PMID: 34318464 DOI: 10.1055/a-1528-2721] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
Silymarin is a standardized extract obtained from seeds of Silybum marianum (SM) belonging to the family Asteraceae. It is a flavonolignan complex and consists of various compounds like silybin A silybin B, isosilybin A, isosilybin B, silydianin, silychristin and isosilychristin. Silybin is the major active component present in 60-70% of the silymarin extract. It has been used traditionally for the treatment of various liver disorders like cirrhosis, jaundice, and hepatitis. Silymarin possesses antioxidant and anti-inflammatory properties and is responsible for its antitumor activity. Other than hepatoprotective effect SM also possesses renoprotective, anti-diabetic, neuroprotective, hypolipidemic, anti-atherosclerosis and cardioprotective effects. Rather antimicrobial property of silymarin was observed against specific microbes, fungi, and viruses. This manuscript covered recent preclinical and clinical evidence of specific components silybin, responsible for its efficacy and about clinical studies has been conducted so far, which proven it's safety and offers mild effect like nausea, diarrhea and bloating. This review specifically focused on recent updates on its active components therapeutic applications against complicated ailments not covered in earlier reports.
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Affiliation(s)
- Anas Islam
- Faculty of Pharmacy, Integral University, Lucknow, Uttar Pradesh, India
| | - Anuradha Mishra
- Faculty of Pharmacy, Integral University, Lucknow, Uttar Pradesh, India
| | - Md Aftab Siddiqui
- Faculty of Pharmacy, Integral University, Lucknow, Uttar Pradesh, India
| | - Saman Siddiquie
- Faculty of Pharmacy, Integral University, Lucknow, Uttar Pradesh, India
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The effect of silymarin on liver enzymes and antioxidant status in trauma patients in the intensive care unit: a randomized double blinded placebo-controlled clinical trial. Clin Exp Hepatol 2021; 7:149-155. [PMID: 34295981 PMCID: PMC8284169 DOI: 10.5114/ceh.2021.107067] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Accepted: 01/24/2021] [Indexed: 01/09/2023] Open
Abstract
Aim of the study This study was conducted to investigate the positive effect of silymarin on liver enzymes and antioxidant status in trauma patients with elevated liver enzymes due to trauma-induced liver injury, admitted to the intensive care unit. Material and methods This one-year, randomized, double-blinded, placebo-controlled clinical trial was conducted on 90 trauma patients. The participants were assigned to either receiving Livergol tablets containing 140 mg of silymarin or 140 mg of placebo three times daily for 14 days. Liver enzymes, including aspartate transaminase (AST), alanine transaminase (ALT) and alkaline phosphatase (ALP), were measured at baseline and days 3, 7, 9 and 14 after intervention. Also, antioxidant markers were measured at baseline and day 14 after treatment. Results Receiving silymarin supplement significantly lowered the liver enzymes, compared to placebo (p < 0.05). The mean serum level of malondialdehyde (MDA) was significantly decreased and the mean serum levels of total antioxidant capacity (TAC) and thiol groups were significantly increased in the silymarin group from baseline to day 14. In the placebo group, mean serum levels of MDA and thiol groups were significantly increased, while serum level of TAC was not significantly changed at day 14, compared to baseline. Also, the mean serum level of MDA was significantly lower, while the serum levels of thiol groups and TAC were significantly higher in the silymarin group. Conclusions Silymarin supplementation significantly improved some antioxidant markers (TAC and thiol) and decreased liver enzymes in patients with trauma-induced liver injury.
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21
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Becker MW, Schwambach KH, Lunardelli M, Blatt CR. Overview of drug induced liver injury in Brazil: What is the role of public health policy on the evidence? World J Gastrointest Pharmacol Ther 2021; 12:40-55. [PMID: 34046243 PMCID: PMC8134851 DOI: 10.4292/wjgpt.v12.i3.40] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Revised: 01/20/2021] [Accepted: 04/25/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Adverse drug reactions are responsible for increased costs and morbidity in the health system. Hepatotoxicity can be induced both by non-prescription drugs and by those used for chronic diseases. It is the main cause of safety-related drug marketing withdrawals and could be responsible for irreversible and fatal injuries. AIM To identify and to summarize Brazilian studies reporting the drug-induced liver injury. METHODS A systematic review of Brazilian studies was carried out until June 2020. It was found 32 studies, being 10 retrospective cohorts, 12 prospective cohorts, 5 cross-sectional, 3 case-control, one case series and one randomized clinical trial. In most studies were investigated tuberculosis patients followed by other infectious conditions like human immunodeficiency virus (HIV) and hepatitis C virus. The hepatotoxicity ranged from one to 57%, led by isoniazid, rifampicin, and pyrazinamide. Few studies reported algorithm to assess causality. In most studies, there were moderate outcomes and it was necessary drug interruption. However, few severe outcomes, such as chronic liver damage and liver transplantation were reported. RESULTS Twenty-two different criteria for hepatotoxicity were found. The great heterogeneity did not allow a meta-analysis. Standardization of parameter of drug-induced liver injury and greater effort in pharmacovigilance could contribute to learn more about drug-induced liver injury (DILI)'s epidemiology in Brazil. CONCLUSION The development of strategic public health policies seems to have an influence on the DILI scientific evidence in Brazil due to main studies are in HIV and tuberculosis line care, two strategic health policies in Brazil.
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Affiliation(s)
- Matheus William Becker
- Graduate Program in Medicine-Hepatology, Federal University of Health Sciences of Porto Alegre, Porto Alegre 90050-170, RS, Brazil
| | - Karin Hepp Schwambach
- Graduate Program in Medicine-Hepatology, Federal University of Health Sciences of Porto Alegre, Porto Alegre 90050-170, RS, Brazil
| | - Michele Lunardelli
- Graduate Program in Medicine-Hepatology, Federal University of Health Sciences of Porto Alegre, Porto Alegre 90050-170, RS, Brazil
| | - Carine Raquel Blatt
- Graduate Program in Medicine-Hepatology, Federal University of Health Sciences of Porto Alegre, Porto Alegre 90050-170, RS, Brazil
- Pharmacoscience Department, Federal University of Health Sciences of Porto Alegre, Porto Alegre 90050-170, RS, Brazil
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22
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Villanueva-Paz M, Morán L, López-Alcántara N, Freixo C, Andrade RJ, Lucena MI, Cubero FJ. Oxidative Stress in Drug-Induced Liver Injury (DILI): From Mechanisms to Biomarkers for Use in Clinical Practice. Antioxidants (Basel) 2021; 10:390. [PMID: 33807700 PMCID: PMC8000729 DOI: 10.3390/antiox10030390] [Citation(s) in RCA: 55] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Accepted: 03/02/2021] [Indexed: 12/11/2022] Open
Abstract
Idiosyncratic drug-induced liver injury (DILI) is a type of hepatic injury caused by an uncommon drug adverse reaction that can develop to conditions spanning from asymptomatic liver laboratory abnormalities to acute liver failure (ALF) and death. The cellular and molecular mechanisms involved in DILI are poorly understood. Hepatocyte damage can be caused by the metabolic activation of chemically active intermediate metabolites that covalently bind to macromolecules (e.g., proteins, DNA), forming protein adducts-neoantigens-that lead to the generation of oxidative stress, mitochondrial dysfunction, and endoplasmic reticulum (ER) stress, which can eventually lead to cell death. In parallel, damage-associated molecular patterns (DAMPs) stimulate the immune response, whereby inflammasomes play a pivotal role, and neoantigen presentation on specific human leukocyte antigen (HLA) molecules trigger the adaptive immune response. A wide array of antioxidant mechanisms exists to counterbalance the effect of oxidants, including glutathione (GSH), superoxide dismutase (SOD), catalase, and glutathione peroxidase (GPX), which are pivotal in detoxification. These get compromised during DILI, triggering an imbalance between oxidants and antioxidants defense systems, generating oxidative stress. As a result of exacerbated oxidative stress, several danger signals, including mitochondrial damage, cell death, and inflammatory markers, and microRNAs (miRNAs) related to extracellular vesicles (EVs) have already been reported as mechanistic biomarkers. Here, the status quo and the future directions in DILI are thoroughly discussed, with a special focus on the role of oxidative stress and the development of new biomarkers.
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Affiliation(s)
- Marina Villanueva-Paz
- Unidad de Gestión Clínica de Gastroenterología, Servicio de Farmacología Clínica, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, CIBERehd, 29071 Málaga, Spain; (M.V.-P.); (M.I.L.)
| | - Laura Morán
- Department of Immunology, Ophthalmology and ENT, Complutense University School of Medicine, 28040 Madrid, Spain; (L.M.); (N.L.-A.)
- Health Research Institute Gregorio Marañón (IiSGM), 28009 Madrid, Spain
| | - Nuria López-Alcántara
- Department of Immunology, Ophthalmology and ENT, Complutense University School of Medicine, 28040 Madrid, Spain; (L.M.); (N.L.-A.)
| | - Cristiana Freixo
- CINTESIS, Center for Health Technology and Services Research, do Porto University School of Medicine, 4200-319 Porto, Portugal;
| | - Raúl J. Andrade
- Unidad de Gestión Clínica de Gastroenterología, Servicio de Farmacología Clínica, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, CIBERehd, 29071 Málaga, Spain; (M.V.-P.); (M.I.L.)
| | - M Isabel Lucena
- Unidad de Gestión Clínica de Gastroenterología, Servicio de Farmacología Clínica, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, CIBERehd, 29071 Málaga, Spain; (M.V.-P.); (M.I.L.)
| | - Francisco Javier Cubero
- Department of Immunology, Ophthalmology and ENT, Complutense University School of Medicine, 28040 Madrid, Spain; (L.M.); (N.L.-A.)
- 12 de Octubre Health Research Institute (imas12), 28041 Madrid, Spain
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Prevention and management of idiosyncratic drug-induced liver injury: Systematic review and meta-analysis of randomised clinical trials. Pharmacol Res 2021; 164:105404. [DOI: 10.1016/j.phrs.2020.105404] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Revised: 12/18/2020] [Accepted: 12/18/2020] [Indexed: 02/06/2023]
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Singh AK, Verma S, Kumar-M P, Soni H, Sharma S, Sharma S, Patil A, Sharma V. Appropriate chemopreventive strategy for anti-tubercular therapy related liver injury is unsettled: Results from a systematic review and network meta-analysis. Expert Rev Clin Pharmacol 2020; 13:1253-1262. [PMID: 33043729 DOI: 10.1080/17512433.2020.1835468] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND Role of chemoprophylaxis for prevention of antitubercular therapy-related drug-induced liver injury (ATT-DILI) is uncertain. METHODS Electronic databases were searched for randomized trials reporting on chemoprophylaxis agents for prevention of ATT-DILI. We included studies evaluating the role of a drug in comparison to controls/placebo. The primary outcome was the occurrence of ATT-DILI. We performed a Bayesian random-effects network meta-analysis to calculate odds ratios (ORs) and 95% credible intervals (CrI) for those arms where at least two studies were available. Additional comparative studies for these arms were also identified. RESULTS Fourteen studies were identified and seven included in the meta-analysis. The agents used for prevention of ATT-DILI were silymarin/silibinin (4 trials), N-acetylcysteine (NAC) (3 studies), herbal preparations (5 studies) and one study each for cholecalciferol and carnitine. Compared with controls/placebo, the odds of occurrence of hepatotoxicity with NAC was 7 * 10-17 (95% CrI: 2.8 * 10-53, 0.0053) and Silymarin was 0.68 (95% CrI: 0.084, 4.6). NAC had the highest probability of rank 1 (0.99) which was followed by Silymarin (0.004). CONCLUSION N-acetyl cysteine, but not Silymarin/Silibinin, appears to be beneficial in prevention of ATT-DILI. However, the results were limited by the possible risk of bias in included studies, variable definitions of ATT-DILI and limited number and category of patients.
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Affiliation(s)
- Anupam Kumar Singh
- Department of Gastroenterology, Postgraduate Institute of Medical Education and Research , Chandigarh, India
| | - Suhang Verma
- Department of Gastroenterology, Postgraduate Institute of Medical Education and Research , Chandigarh, India
| | - Praveen Kumar-M
- Department of Pharmacology, Postgraduate Institute of Medical Education and Research , Chandigarh, India
| | - Hariom Soni
- Department of Pharmacology, Postgraduate Institute of Medical Education and Research , Chandigarh, India
| | | | - Swati Sharma
- Department of Pharmacology, Postgraduate Institute of Medical Education and Research , Chandigarh, India
| | - Amol Patil
- Department of Pharmacology, Postgraduate Institute of Medical Education and Research , Chandigarh, India
| | - Vishal Sharma
- Department of Gastroenterology, Postgraduate Institute of Medical Education and Research , Chandigarh, India
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An Evaluation of the In Vitro Roles and Mechanisms of Silibinin in Reducing Pyrazinamide- and Isoniazid-Induced Hepatocellular Damage. Int J Mol Sci 2020; 21:ijms21103714. [PMID: 32466226 PMCID: PMC7279482 DOI: 10.3390/ijms21103714] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Revised: 05/19/2020] [Accepted: 05/22/2020] [Indexed: 02/06/2023] Open
Abstract
Tuberculosis remains a significant infectious lung disease that affects millions of patients worldwide. Despite numerous existing drug regimens for tuberculosis, drug-induced liver injury is a major challenge that limits the effectiveness of these therapeutics. Two drugs that form the backbone of the commonly administered quadruple antitubercular regimen, that is, pyrazinamide (PZA) and isoniazid (INH), are associated with such hepatotoxicity. Yet, we lack safe and effective alternatives to the antitubercular regimen. Consequently, current research largely focuses on exploiting the hepatoprotective effect of nutraceutical compounds as complementary therapy. Silibinin, a herbal product widely believed to protect against various liver diseases, potentially provides a useful solution given its hepatoprotective mechanisms. In our study, we identified silibinin’s role in mitigating PZA- and INH-induced hepatotoxicity and elucidated a deeper mechanistic understanding of silibinin’s hepatoprotective ability. Silibinin preserved the viability of human foetal hepatocyte line LO2 when co-administered with 80 mM INH and decreased apoptosis induced by a combination of 40 mM INH and 10 mM PZA by reducing oxidative damage to mitochondria, proteins, and lipids. Taken together, this proof-of-concept forms the rational basis for the further investigation of silibinin’s hepatoprotective effect in subsequent preclinical studies and clinical trials.
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Abstract
Silymarin, an extract from milk thistle seeds, has been used for centuries to treat hepatic conditions. Preclinical data indicate that silymarin can reduce oxidative stress and consequent cytotoxicity, thereby protecting intact liver cells or cells not yet irreversibly damaged. Eurosil 85® is a proprietary formulation developed to maximize the oral bioavailability of silymarin. Most of the clinical research on silymarin has used this formulation. Silymarin acts as a free radical scavenger and modulates enzymes associated with the development of cellular damage, fibrosis and cirrhosis. These hepatoprotective effects were observed in clinical studies in patients with alcoholic or non-alcoholic fatty liver disease, including patients with cirrhosis. In a pooled analysis of trials in patients with cirrhosis, silymarin treatment was associated with a significant reduction in liver-related deaths. Moreover, in patients with diabetes and alcoholic cirrhosis, silymarin was also able to improve glycemic parameters. Patients with drug-induced liver injuries were also successfully treated with silymarin. Silymarin is generally very well tolerated, with a low incidence of adverse events and no treatment-related serious adverse events or deaths reported in clinical trials. For maximum benefit, treatment with silymarin should be initiated as early as possible in patients with fatty liver disease and other distinct liver disease manifestations such as acute liver failure, when the regenerative potential of the liver is still high and when removal of oxidative stress, the cause of cytotoxicity, can achieve the best results.
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Affiliation(s)
- Anton Gillessen
- Department of Internal Medicine, Sacred Heart Hospital, Muenster, Germany.
| | - Hartmut H-J Schmidt
- Department of Medicine B for Gastroenterology and Hepatology, University Hospital Muenster, Muenster, Germany
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Sahu N, Mishra G, Chandra HK, Nirala SK, Bhadauria M. Naringenin mitigates antituberculosis drugs induced hepatic and renal injury in rats. J Tradit Complement Med 2020; 10:26-35. [PMID: 31956555 PMCID: PMC6957811 DOI: 10.1016/j.jtcme.2019.01.001] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2018] [Revised: 01/02/2019] [Accepted: 01/03/2019] [Indexed: 01/24/2023] Open
Abstract
Tuberculosis is one of the deadly diseases, which can be well treated by antituberculosis drugs (ATDs) i.e. isoniazid, rifampicin, pyrazinamide and ethambutol. These drugs also lead to severe hepatic and renal injury. The present study was designed to investigate efficacy of naringenin against ATDs induced hepato-renal injury. Rats were administered with ATDs for 8 weeks (3 day/week) followed by naringenin at three different doses (10, 20 and 40 mg/kg) conjointly for 8 weeks (3 days/week) orally. Silymarin (50 mg/kg) was used as positive control in the study. Hepatic and renal injury was measured by increased level of serological parameters such as aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, bilirubin, urea, uric acid and creatinine. The toxic effect of ATDs was also indicated by significant increase in lipid peroxidation along with decline in GSH, catalase and superoxide dismutase activity in liver and kidney tissues. Treatment with naringenin encountered ATDs induced injury as evident by significant reversal of biochemical indices towards their respective control in a dose dependent manner. Histopathological observations also supported biochemical findings. Assessment of TNF-α indicated therapeutic efficacy of naringenin at molecular level. Thus, results of this study clearly showed that naringenin possess protective role against ATDs induced hepato-renal injury and to take naringenin supplementation as food may be worthwhile to reduce ATDs induced hepato-renal injury.
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Affiliation(s)
- Nisha Sahu
- Toxicology and Pharmacology Laboratory, Department of Zoology, Guru Ghasidas University, Bilaspur, 495009 (CG), India
| | - Gita Mishra
- Toxicology and Pharmacology Laboratory, Department of Zoology, Guru Ghasidas University, Bilaspur, 495009 (CG), India
| | - Hemeshwer Kumar Chandra
- Toxicology and Pharmacology Laboratory, Department of Zoology, Guru Ghasidas University, Bilaspur, 495009 (CG), India
| | - Satendra Kumar Nirala
- Laboratory of Natural Products, Department of Rural Technology and Social Development, Guru Ghasidas University, Bilaspur, 495009 (CG), India
| | - Monika Bhadauria
- Toxicology and Pharmacology Laboratory, Department of Zoology, Guru Ghasidas University, Bilaspur, 495009 (CG), India
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Sieniawska E, Maciejewska-Turska M, Świątek Ł, Xiao J. Plant-based Food Products for Antimycobacterial Therapy. EFOOD 2020. [DOI: 10.2991/efood.k.200418.001] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/01/2022] Open
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Wang Y, Wang Z, Gao M, Zhong H, Chen C, Yao Y, Zhang Z, Zhang X, Li F, Zhang J, Gu HM, Chen Y, Tang J, Zhong W, Zeng M, Mao Y. Efficacy and safety of magnesium isoglycyrrhizinate injection in patients with acute drug-induced liver injury: A phase II trial. Liver Int 2019; 39:2102-2111. [PMID: 31379118 DOI: 10.1111/liv.14204] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2018] [Revised: 07/19/2019] [Accepted: 07/29/2019] [Indexed: 12/11/2022]
Abstract
BACKGROUND Drug-induced liver injury (DILI) is the most common reason for a drug to be withdrawn from the market. Apart from stopping the offending drug, no regimens are available for treating idiosyncratic DILI in clinical practice. METHODS We carried out a randomized, double-blind, multidoses, active drug controlled, multicentre phase II trial to assess the safety and efficacy of the study drug, magnesium isoglycyrrhizinate (MgIG), as compared to tiopronin, a standard therapy for DILI in China. The primary outcome was the proportion of alanine aminotransferase (ALT) normalization at week 4 after study drug administration. Logistic regression was used to examine the odds of ALT normalization between low dose (Group A) and high dose (Group B) vs active control (Group C). RESULTS One hundred and seventy-four eligible subjects were randomized and enrolled into three groups: 59 in group A, 56 in group B and 59 in group C. It was shown that group A and group B lowered ALT level even at early stage of study drug administration; when compared with Group C (61.02%), the proportions of ALT normalization at week 4 were significantly greater in Group A (84.75%, P = .0029) and Group B (85.71%, P = .0037) respectively. The results from the univariate logistic model showed that the odds of ALT normalized among subjects in Group A were about 3.6 times greater (OR = 3.55, 95% CI: 1.47-8.57, P = .0049) than subjects in Group C. Similar effect was observed among subjects in Group B (OR = 3.83, 95% CI: 1.54-9.55, P = .0039). CONCLUSIONS This trial provided preliminary evidence that MgIG is an effective and safe treatment for patients with acute DILI.
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Affiliation(s)
- Yongfeng Wang
- Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Zhenghua Wang
- Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Mengqiu Gao
- Division of Tuberculosis, Beijing Chest Hospital, Beijing, China
| | - Haijun Zhong
- Division of Tumor, Zhejiang Provincial Tumor Hospital, Hangzhou, China
| | - Chengwei Chen
- Liver Disease Center of Naval 905 Hospital, Shanghai, China
| | - Yang Yao
- Division of Tumor, Shanghai Sixth People's Hospital, Shanghai, China
| | - Zhongshun Zhang
- Division of Tuberculosis, Shanghai Pulmonary Hospital, Shanghai, China
| | - Xia Zhang
- Division of Tuberculosis, Nanjing Chest Hospital, Nanjing, China
| | - Fujian Li
- Division of Tuberculosis, Zhejiang Hospital of Integrated Traditional Chinese and Western Medicine, Hangzhou, China
| | | | - Hong-Mei Gu
- Chia Tai Tianqing Pharmaceutical Group Co., Ltd, Nanjing, China
| | - Yingxuan Chen
- Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jieting Tang
- Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Wei Zhong
- Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Minde Zeng
- Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yimin Mao
- Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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Huang X, Lee F, Teng Y, Lingam CB, Chen Z, Sun M, Song Z, Balachander GM, Leo HL, Guo Q, Shah I, Yu H. Sequential drug delivery for liver diseases. Adv Drug Deliv Rev 2019; 149-150:72-84. [PMID: 31734169 DOI: 10.1016/j.addr.2019.11.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2019] [Revised: 11/03/2019] [Accepted: 11/04/2019] [Indexed: 12/12/2022]
Abstract
The liver performs critical physiological functions such as metabolism/detoxification and blood homeostasis/biliary excretion. A high degree of blood access means that a drug's resident time in any cell is relatively short. This short drug exposure to cells requires local sequential delivery of multiple drugs for optimal efficacy, potency, and safety. The high metabolism and excretion of drugs also impose both technical challenges and opportunities to sequential drug delivery. This review provides an overview of the sequential events in liver regeneration and the related liver diseases. Using selected examples of liver cancer, hepatitis B viral infection, fatty liver diseases, and drug-induced liver injury, we highlight efforts made for the sequential delivery of small and macromolecular drugs through different biomaterials, cells, and microdevice-based delivery platforms that allow fast delivery kinetics and rapid drug switching. As this is a nascent area of development, we extrapolate and compare the results with other sequential drug delivery studies to suggest possible application in liver diseases, wherever appropriate.
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Affiliation(s)
- Xiaozhong Huang
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, MD9-04-11, 2 Medical Drive, Singapore 117593, Singapore; Institute of Bioengineering and Nanotechnology, A*STAR, The Nanos, #06-01, 31 Biopolis Way, Singapore 138669, Singapore
| | - Fan Lee
- Institute of Bioengineering and Nanotechnology, A*STAR, The Nanos, #06-01, 31 Biopolis Way, Singapore 138669, Singapore
| | - Yao Teng
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, MD9-04-11, 2 Medical Drive, Singapore 117593, Singapore; Institute of Bioengineering and Nanotechnology, A*STAR, The Nanos, #06-01, 31 Biopolis Way, Singapore 138669, Singapore
| | - Corey Bryen Lingam
- Department of Biomedical Engineering, National University of Singapore, Engineering Drive 3, Engineering Block 4, #04-08, Singapore 117583, Singapore
| | - Zijian Chen
- Department of Biomedical Engineering, National University of Singapore, Engineering Drive 3, Engineering Block 4, #04-08, Singapore 117583, Singapore; Department of Biomedical Engineering, Southern University of Science and Technology, 1088 Xueyuan Avenue, Shenzhen 518055, China
| | - Min Sun
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, MD9-04-11, 2 Medical Drive, Singapore 117593, Singapore
| | - Ziwei Song
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, MD9-04-11, 2 Medical Drive, Singapore 117593, Singapore; Institute of Bioengineering and Nanotechnology, A*STAR, The Nanos, #06-01, 31 Biopolis Way, Singapore 138669, Singapore
| | - Gowri M Balachander
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, MD9-04-11, 2 Medical Drive, Singapore 117593, Singapore
| | - Hwa Liang Leo
- Department of Biomedical Engineering, National University of Singapore, Engineering Drive 3, Engineering Block 4, #04-08, Singapore 117583, Singapore
| | - Qiongyu Guo
- Department of Biomedical Engineering, Southern University of Science and Technology, 1088 Xueyuan Avenue, Shenzhen 518055, China
| | - Imran Shah
- National Center for Computational Toxicology, United States Environmental Protection Agency, 4930 Old Page Rd., Durham, NC 27703, USA
| | - Hanry Yu
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, MD9-04-11, 2 Medical Drive, Singapore 117593, Singapore; Institute of Bioengineering and Nanotechnology, A*STAR, The Nanos, #06-01, 31 Biopolis Way, Singapore 138669, Singapore; Mechanobiology Institute, National University of Singapore, T-Lab, #05-01, 5A Engineering Drive 1, Singapore 117411, Singapore; CAMP, Singapore-MIT Alliance for Research and Technology, 1 CREATE Way, Level 4 Enterprise Wing, Singapore 138602, Singapore; Gastroenterology Department, Southern Medical University, Guangzhou 510515, China.
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Han W, Duan Z. Different drug metabolism behavior between species in drug-induced hepatotoxicity: limitations and novel resolutions. TOXIN REV 2019. [DOI: 10.1080/15569543.2019.1639060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Affiliation(s)
- Weijia Han
- Difficult and Complicated Liver Diseases and Artificial Liver Center, Beijing Youan Hospital, Capital Medical University, Beijing, China
- Beijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment Research, Beijing, China
| | - Zhongping Duan
- Difficult and Complicated Liver Diseases and Artificial Liver Center, Beijing Youan Hospital, Capital Medical University, Beijing, China
- Beijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment Research, Beijing, China
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Lutfiana NC, van Boven JF, Masoom Zubair MA, Pena MJ, Alffenaar JC. Diabetes mellitus comorbidity in patients enrolled in tuberculosis drug efficacy trials around the world: A systematic review. Br J Clin Pharmacol 2019; 85:1407-1417. [PMID: 30908689 PMCID: PMC6595305 DOI: 10.1111/bcp.13935] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2018] [Revised: 02/24/2019] [Accepted: 03/14/2019] [Indexed: 12/14/2022] Open
Abstract
AIMS With a prevalence of 16%, diabetes mellitus (DM) is one of the most frequent non-communicable comorbidities of tuberculosis (TB). DM is a major risk factor for adverse TB outcomes and may require personalized TB drug dosing regimens. However, information on the inclusion of DM in TB drug trials is lacking. We aimed to assess the percentage of recent TB drug efficacy trials that included DM patients. METHODS A systematic review was performed and reported according to PRISMA guidelines. PubMed, Science Direct, and ClinicalTrials.gov databases were systematically searched for TB drug trials published between 1 January 2012 and 12 September 2017. Primary outcome was the percentage of TB drug trials performed around the world that included DM patients. RESULTS Out of the included 41 TB drug trials, 12 (29.3%) reported DM comorbidity among the study participants. Nine trials (21.9%) excluded all patients with DM comorbidity, ten (24.4%) excluded only insulin-dependent or uncontrolled DM, and 10 (24.4%) did not mention whether DM was included or excluded. Of the 12 trials that included DM comorbidity, the majority did not report the diagnostic criteria for DM and none reported outcomes in the DM subpopulation. Inclusion of DM was higher in drug-resistant-TB trials (67%, P = .003, vs drug-susceptible) and trials performed in Asia (60%, P = .006, vs Africa). CONCLUSIONS Fewer than 1/3 recent TB drug trials reported the inclusion of DM. To better reflect real-world DM prevalence and differential TB drug effectiveness, inclusion of DM patients requires increased attention for future TB drug trials.
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Affiliation(s)
- Nurul Cholifah Lutfiana
- Department of Clinical Pharmacy & PharmacologyUniversity of Groningen, University Medical Center GroningenGroningenThe Netherlands
- Faculty of Medicine, Department of BiomedicineBrawijaya UniversityMalangIndonesia
| | - Job F.M. van Boven
- Department of Clinical Pharmacy & PharmacologyUniversity of Groningen, University Medical Center GroningenGroningenThe Netherlands
| | - Muhammad Asim Masoom Zubair
- Department of Clinical Pharmacy & PharmacologyUniversity of Groningen, University Medical Center GroningenGroningenThe Netherlands
- Department of PharmacyThe Islamia University of BahawalpurBahawalpurPakistan
| | - Michelle J. Pena
- Department of Clinical Pharmacy & PharmacologyUniversity of Groningen, University Medical Center GroningenGroningenThe Netherlands
| | - Jan‐Willem C. Alffenaar
- Department of Clinical Pharmacy & PharmacologyUniversity of Groningen, University Medical Center GroningenGroningenThe Netherlands
- Faculty of Medicine and Health, School of PharmacyUniversity of SydneySydneyAustralia
- Westmead HospitalSydneyAustralia
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Soleimani V, Delghandi PS, Moallem SA, Karimi G. Safety and toxicity of silymarin, the major constituent of milk thistle extract: An updated review. Phytother Res 2019; 33:1627-1638. [PMID: 31069872 DOI: 10.1002/ptr.6361] [Citation(s) in RCA: 99] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2019] [Revised: 03/05/2019] [Accepted: 03/16/2019] [Indexed: 02/06/2023]
Abstract
Milk thistle (Silybum marianum) is a medicinal plant from the Asteraceae family. Silymarin is the major constituent of milk thistle extract and is a mixture of some flavonolignans such as silybin, which is the most active component of silymarin. It is most commonly known for its hepatoprotective effect. Also, studies have shown other therapeutic effects such as anticancer, anti-Alzheimer, anti-Parkinson, and anti-diabetic, so its safety is very important. It has no major toxicity in animals. Silymarin was mutagen in Salmonella typhimurium strains in the presence of metabolic enzymes. Silybin, silydianin, and silychristin were not cytotoxic and genotoxic at concentration of 100 μM. Silymarin is safe in humans at therapeutic doses and is well tolerated even at a high dose of 700 mg three times a day for 24 weeks. Some gastrointestinal discomforts occurred like nausea and diarrhea. One clinical trial showed silymarin is safe in pregnancy, and there were no anomalies. Consequently, caution should be exercised during pregnancy, and more studies are needed especially in humans. Silymarin has low-drug interactions, and it does not have major effects on cytochromes P-450. Some studies demonstrated that the use of silymarin must be with caution when co-administered with narrow therapeutic window drugs.
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Affiliation(s)
- Vahid Soleimani
- School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
- Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Parisa Sadat Delghandi
- School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
- Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyed Adel Moallem
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, University of Ahl Al Bayt, Karbala, Iraq
- Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University ofMedical Sciences, Mashhad, Iran
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alzahraa University, Karbala, Iraq
| | - Gholamreza Karimi
- School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
- Pharmaceutical Research Center, Institute of Pharmaceutical Technology, Mashhad University of Medical Sciences, Mashhad, Iran
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Rodríguez-Flores EM, Mata-Espinosa D, Barrios-Payan J, Marquina-Castillo B, Castañón-Arreola M, Hernández-Pando R. A significant therapeutic effect of silymarin administered alone, or in combination with chemotherapy, in experimental pulmonary tuberculosis caused by drug-sensitive or drug-resistant strains: In vitro and in vivo studies. PLoS One 2019; 14:e0217457. [PMID: 31145751 PMCID: PMC6542514 DOI: 10.1371/journal.pone.0217457] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2018] [Accepted: 05/13/2019] [Indexed: 12/11/2022] Open
Abstract
For many years, tuberculosis (TB) has been a major public health problem worldwide. Advances for treatment and eradication have been very limited. Silymarin (Sm) is a natural product with antioxidant and hepatoprotective activities that has been proposed as a complementary medicine to reduce the liver injury produced by the conventional anti-TB chemotherapy. Sm also has immunoregulatory and microbicide properties. In this study, we determined the effect of Sm on the growth control of mycobacteria. In vitro studies showed that Sm and Silibinin (the principal active compound of Sm) have microbicidal activity against drug-sensitive and multidrug-resistant (MDR) mycobacteria, induce the production of protective cytokines from infected macrophages, and improve the growth control of mycobacteria (p ≤ 0.0001). Studies in vivo using a model of progressive pulmonary TB in BALB/c mice infected with drug-sensitive or MDR mycobacteria have shown that Sm induces significant expression of Th-1 cytokines such as IFN-γ and IL-12 as well as TNFα, which produce significant therapeutic activity when administered alone and apparently have a synergistic effect with chemotherapy. These results suggest that Sm has a bactericidal effect and can contribute to the control and establishment of a TH1 protective immune response against mycobacterial infection. Thus, it seems that this flavonoid has a promising potential as adjuvant therapy in the treatment of TB.
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Affiliation(s)
- Edén M. Rodríguez-Flores
- Department of Pathology, Experimental Pathology Section, National Institute of Medical Sciences and Nutrition ‘‘Salvador Zubiran”, Mexico City, Mexico
- Genomic Sciences Program, Autonomous University of México City, Mexico City, México
| | - Dulce Mata-Espinosa
- Department of Pathology, Experimental Pathology Section, National Institute of Medical Sciences and Nutrition ‘‘Salvador Zubiran”, Mexico City, Mexico
| | - Jorge Barrios-Payan
- Department of Pathology, Experimental Pathology Section, National Institute of Medical Sciences and Nutrition ‘‘Salvador Zubiran”, Mexico City, Mexico
| | - Brenda Marquina-Castillo
- Department of Pathology, Experimental Pathology Section, National Institute of Medical Sciences and Nutrition ‘‘Salvador Zubiran”, Mexico City, Mexico
| | | | - Rogelio Hernández-Pando
- Department of Pathology, Experimental Pathology Section, National Institute of Medical Sciences and Nutrition ‘‘Salvador Zubiran”, Mexico City, Mexico
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Prophylactic Therapy of Silymarin (Milk Thistle) on Antituberculosis Drug-Induced Liver Injury: A Meta-Analysis of Randomized Controlled Trials. Can J Gastroenterol Hepatol 2019; 2019:3192351. [PMID: 30733935 PMCID: PMC6348824 DOI: 10.1155/2019/3192351] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2018] [Revised: 12/12/2018] [Accepted: 12/31/2018] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Prophylactic therapy with silymarin to prevent the development of antituberculosis drug-induced liver injury (anti-TB DILI) has been under debate. We aimed to evaluate the effect of silymarin in the prevention of anti-TB DILI. METHODS We searched MEDLINE, PubMed, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) up to 30th November 2018. Randomized controlled trials (RCTs) that compared silymarin and placebo to prevent anti-TB DILI were included. All statistical analyses were conducted using STATA 12.0 software. Standardized mean difference (SMD) and risk ratio (RR) with 95% confidence intervals (CIs) were used to evaluate the effect of silymarin. The quality of included studies was assessed according to Cochrane handbook. Funnel plots and Egger's tests were carried out to evaluate publication bias. Sensitivity analysis was conducted to assess the influence of each study. RESULTS A total of 1198 patients from five RCTs (585 with silymarin and 613 with placebo groups) were included. Overall, silymarin significantly reduced the occurrence of anti-TB DILI at week 4 [RR: 0.33, 95% CI (0.15, 0.75)]. In addition, silymarin exerted protective effect on liver function in patients undergoing anti-TB drugs [SMD = - 0.15, 95% CI (-0.24, -0.07), P < 0.001 (ALT); SMD =-0.14, 95% CI (-0.23, -0.06), P = 0.001(AST); SMD =-0.12, 95% CI (-0.20, -0.03), P = 0.008 (ALP)]. Silymarin led to similar AEs in placebo groups [OR: 1.09, 95% CI (0.86, 1.39), P = 0.47]. CONCLUSION Prophylactic therapy of silymarin is contributed to a noticeably reduced risk of development of anti-TB DILI four weeks after the initiation. In addition, silymarin significantly improved the liver function in patients who are receiving anti-TB drugs.
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Marjani M, Fahim F, Sadr M, Kazempour Dizaji M, Moniri A, Khabiri S, Tabarsi P, Velayati AA. Evaluation of Silymarin for management of anti-tuberculosis drug induced liver injury: a randomized clinical trial. GASTROENTEROLOGY AND HEPATOLOGY FROM BED TO BENCH 2019; 12:138-142. [PMID: 31191838 PMCID: PMC6536020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/02/2022]
Abstract
AIM This study was performed to evaluate the potential efficacy of silymarin in the management of anti-tuberculosis medication's induced liver injury. BACKGROUND Hepatic toxicity is the most serious complication in treatment of tuberculosis. METHODS In a randomized double blind clinical trial (ACTRN12610000643077), 55 cases with hepatotoxicity caused by anti-tuberculosis drugs were divided into two groups. Informed consents were obtained. The intervention group received silymarin and the control group received placebo. Severity of liver injury, the duration necessary for normalization of liver function and hospital stay were compared between the two groups. RESULTS There was not any statistically significant difference in the rate of adverse effects between silymarin and placebo groups. CONCLUSION Although silymarin is considered a safe herbal medication, it was not effective to treat hepatic toxicity of anti-tuberculosis drugs.
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Affiliation(s)
- Majid Marjani
- Clinical Tuberculosis and Epidemiology Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Masih Daneshvari Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Fanak Fahim
- Department of Clinical Pharmacy, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Makan Sadr
- Virology Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Masih Daneshvari Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mehdi Kazempour Dizaji
- Mycobacteriology Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Masih Daneshvari Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Afshin Moniri
- Virology Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Masih Daneshvari Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Shadi Khabiri
- Clinical Tuberculosis and Epidemiology Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Masih Daneshvari Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Payam Tabarsi
- Clinical Tuberculosis and Epidemiology Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Masih Daneshvari Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Abenavoli L, Izzo AA, Milić N, Cicala C, Santini A, Capasso R. Milk thistle (Silybum marianum): A concise overview on its chemistry, pharmacological, and nutraceutical uses in liver diseases. Phytother Res 2018; 32:2202-2213. [PMID: 30080294 DOI: 10.1002/ptr.6171] [Citation(s) in RCA: 229] [Impact Index Per Article: 32.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2018] [Revised: 07/06/2018] [Accepted: 07/09/2018] [Indexed: 12/17/2022]
Abstract
Milk thistle (MT; Silybum marianum), a member of the Asteraceae family, is a therapeutic herb with a 2,000-year history of use. MT fruits contain a mixture of flavonolignans collectively known as silymarin, being silybin (also named silibinin) the main component. This article reviews the chemistry of MT, the pharmacokinetics and bioavailability, the pharmacologically relevant actions for liver diseases (e.g., anti-inflammatory, immunomodulating, antifibrotic, antioxidant, and liver-regenerating properties) as well as the clinical potential in patients with alcoholic liver disease, nonalcoholic fatty liver disease, viral hepatitis, drug-induced liver injury, and mushroom poisoning. Overall, literature data suggest that, despite encouraging preclinical data, further well-designed randomized clinical trials are needed to fully substantiate the real value of MT preparations in liver diseases.
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Affiliation(s)
- Ludovico Abenavoli
- Department of Health Sciences, University Magna Graecia, Catanzaro, Italy
| | - Angelo A Izzo
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Natasa Milić
- Department of Pharmacy, Faculty of Medicine, University of Novi Sad, Novi Sad, Serbia
| | - Carla Cicala
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Antonello Santini
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Raffaele Capasso
- Department of Agricultural Sciences, University of Naples Federico II, Naples, Italy
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A comparison of the effects of thymoquinone, silymarin and N-acetylcysteine in an experimental hepatotoxicity. Biomed Pharmacother 2018; 106:1705-1712. [PMID: 30119245 DOI: 10.1016/j.biopha.2018.07.125] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2018] [Revised: 07/05/2018] [Accepted: 07/24/2018] [Indexed: 12/19/2022] Open
Abstract
This study investigated the effects of thymoquinone, silymarin, and N-acetylcysteine in a rat model with carbon tetrachloride (CCl4)-induced hepatotoxicity. Although numerous similar studies are available, we aimed to compare the efficacy of these agents by considering N-acetylcysteine as a reference compound. A total of 50 male Wistar albino rats were randomly designated as 5 groups: Group I, CCl4; group II, thymoquinone and CCl4; group III, silymarin and CCl4; group IV, N-acetylcysteine and CCl4; group V, control group. CCl4 was administered intraperitoneally at a dose of 1.5 mL/kg (a mixture of CCl4: olive oil, 1:2) twice a week. Thymoquinone was administered at a dose of 10 mg/kg, silymarin was administered at a dose of 100 mg/kg, and N-acetylcysteine was administered at a dose of 100 mg/kg by daily intraperitoneal injection. At the end of four weeks, blood and liver tests were analyzed. The results were evaluated statistically via the one-way ANOVA test. A p-value <0.05 was considered statistically significant. Thymoquinone, silymarin, and N-acetylcysteine improved the levels of alanine aminotransferase, tumor necrosis factor-α, platelet-derived growth factor-BB, and interleukin-6, which were increased by CCl4. Thymoquinone and silymarin showed the positive increase in liver glutathione levels. Thymoquinone, silymarin, and N-acetylcysteine improved blood total oxidant status. In the histological examinations of liver tissue, thymoquinone decreased necrosis, and inflammation. The most positive decrease in the α-smooth muscle actin-stained hepatic stellate cell count was only observed with thymoquinone. These findings suggest that thymoquinone, silymarin, and N-acetylcysteine have potential for the treatment of diseases causing liver injury. Among these agents, thymoquinone showed the best results on most of the parameters. Since TQ appears to be at least as effective as SM and NAC in our in-vitro study, we propose that it is time for clinical studies with thymoquinone on hepatotoxicity.
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de Avelar CR, Pereira EM, de Farias Costa PR, de Jesus RP, de Oliveira LPM. Effect of silymarin on biochemical indicators in patients with liver disease: Systematic review with meta-analysis. World J Gastroenterol 2017; 23:5004-5017. [PMID: 28785154 PMCID: PMC5526770 DOI: 10.3748/wjg.v23.i27.5004] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2017] [Revised: 04/06/2017] [Accepted: 06/18/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluate the effect of silymarin on the serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma glutamyl transpeptidase (γGT) in patients with liver diseases. METHODS A systematic review with meta-analysis of ramdomized and controlled clinical trials was performed, evaluating the effects of sylimarin in patients with hepatic diseases, published by January 31, 2016. Clinical trials were sought on the basis of The Cochrane Central Register of Controlled Trials in the Cochrane Library, PubMed/Medline, Scopus, Web of Science, Lilacs and Clinical Trials. The trials with adult and elderly patients of both sexes, with Liver Diseases who took oral silymarin supplementation, as extract or isolated, as well as Silymarin combined with other nutrients, were included. The trials should provide information about the intervention, such as dosages and detailing of the product used, besides the mean and standard deviation of serum levels of ALT, AST and γGT of the baseline and at the end of the intervention. RESULTS An amount of 10904 publications were identified. From those, only 17 were included in the systematic review and 6 in the meta-analysis, according to the used selection criteria. In this meta-analysis, the results indicated a reduction of 0.26 IU/mL (95%CI: -0.46-0.07, P = 0.007) at the level of ALT and 0.53 IU/mL (95%CI: -0.74-0.32, P = 0.000) at the serum levels of AST after using the silymarin, both, statistically significant, but with no clinical relevance. There was no significant change in the γGT levels. Subgroup analyzes were also performed for the biochemical markers in relation to the type of intervention, whether silymarin isolated or associated with other nutrients and the time of intervention (whether ≥ 6 mo or < 6 mo). Significant differences were not found. The evaluated studies presented a high degree of heterogeneity and low methodological quality in the carried out analysis. CONCLUSION Silymarin minimally reduced, but without clinical relevance, the serum levels of ALT and AST. It is necessary to carry out studies with more appropriate methodological designs.
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Heo E, Kim DK, Oh SH, Lee JK, Park JH, Chung HS. Effect of Prophylactic Use of Silymarin on Anti-tuberculosis Drugs Induced Hepatotoxicity. Tuberc Respir Dis (Seoul) 2017; 80:265-269. [PMID: 28747959 PMCID: PMC5526953 DOI: 10.4046/trd.2017.80.3.265] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2017] [Revised: 04/04/2017] [Accepted: 04/05/2017] [Indexed: 11/24/2022] Open
Abstract
BACKGROUND The first line of anti-tuberculosis (TB) drugs are the most effective standard of drugs for TB. However, the use of these drugs is associated with hepatotoxicity. Silymarin has protective effects against hepatotoxicity of anti-TB drugs in animal models. This study aims to investigate the protective effect of silymarin on hepatotoxicity caused by anti-TB drugs. METHODS This is a prospective, randomized, double-blind and placebo-controlled study. Patients were eligible if they were 20 years of age or order and started the first-line anti-tuberculosis drugs. Eligible patients were randomized for receiving silymarin or a placebo for the first 4 weeks. The primary outcome was the proportion of patients who showed elevated serum liver enzymes more than 3 times the upper normal limit (UNL) or total bilirubin (TBil) > 2× UNL within the first 8 weeks of anti-TB treatment. RESULTS We enrolled a total of 121 patients who silymarin or a placebo to start their anti-TB treatment, for the first 8 weeks. The proportions of elevated serum liver enzymes more than 3 times of UNL at week 2, week 4, and week 8 did not show any significant difference between the silymarin and placebo groups, at 0% versus 3.6% (p>0.999); 4.4% versus 3.6% (p>0.999); and 8.7% versus 10.8% (p=0.630), respectively. However, patients with TBil >2× ULN at week 8 were significantly low in the silymarin group (0% versus 8.7%, p=0.043). CONCLUSION Our findings did not show silymarin had any significant preventive effect on the hepatotoxicity of anti-TB drugs.
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Affiliation(s)
- Eunyoung Heo
- Department of Internal Medicine, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul, Korea
| | - Deog Kyeom Kim
- Department of Internal Medicine, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul, Korea
| | - So Hee Oh
- Department of Medical Statistics, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul, Korea
| | - Jung-Kyu Lee
- Department of Internal Medicine, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul, Korea
| | - Ju-Hee Park
- Department of Internal Medicine, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul, Korea
| | - Hee Soon Chung
- Department of Internal Medicine, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul, Korea
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Xu L, Zhang F, Xu C, Liu KG, Wu W, Tian YX. Is the Prophylactic Use of Hepatoprotectants Necessary in Anti-Tuberculosis Treatment? Chemotherapy 2017; 62:269-278. [PMID: 28490012 DOI: 10.1159/000465515] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2016] [Accepted: 02/26/2017] [Indexed: 11/19/2022]
Abstract
BACKGROUND Liver injury is one of the serious side effects of anti-tuberculosis (TB) drugs. It is controversial whether hepatoprotectant prophylaxis is efficient and safe in anti-TB treatment, so we aimed to assess the efficacy and safety of hepatoprotectant prophylaxis in patients who had received anti-TB treatment. METHODS PubMed, the Cochrane library, Embase, Ovid, Springer link, Wiley, Elsevier, Web of Science, and the Karger Online Journal were systematically searched prior to April 2016 for articles related to hepatoprotectant prophylaxis in the treatment of TB. A meta-analysis was conducted to estimate the effect of hepatoprotective agents on liver function and adverse events (AEs) in patients who had received anti-TB drugs. The primary outcomes were changes in alanine transaminase (ALT) and aspartate transaminase (AST) levels. The other outcomes were drug-induced liver injury (DILI) and AEs. RESULTS In our review, 6 trials that involved 1,227 patients were included. Our analysis indicated that hepatoprotective agents exerted protective effects on liver function in patients who had received anti-TB drugs (weighted mean difference, WMD = -7.81, 95% CI [-12.26, -3.37], p = 0.0006 [ALT]; WMD = -7.07, 95% CI [-11.43, -2.72], p = 0.001 [AST]) in any age group. However, in the subgroup analysis of treatment duration, the use of hepatoprotective agents was not associated with significant changes in ALT and AST levels after 2 weeks of treatment and exhibited a positive effect on liver function after 4 weeks of treatment. Moreover, the use of hepatoprotectants significantly decreased the number of DILI cases (risk ratio, RR 0.50, 95% CI [0.34-0.73], p = 0.0004). However, the use of hepatoprotectants led to similar AEs in the control groups (RR 1.07, 95% CI [0.82-1.39], p = 0.62). CONCLUSIONS The use of hepatoprotective drugs may prevent liver injury in patients who are receiving anti-TB drugs without any significant AEs 4 weeks after the initiation of hepatoprotective medication.
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Affiliation(s)
- Li Xu
- Department of Pharmacy, The First Affiliated Hospital of Xi'an Medical University, Xi'an, PR China
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Jiménez-Arellanes MA, Gutiérrez-Rebolledo GA, Meckes-Fischer M, León-Díaz R. Medical plant extracts and natural compounds with a hepatoprotective effect against damage caused by antitubercular drugs: A review. ASIAN PAC J TROP MED 2016; 9:1141-1149. [DOI: 10.1016/j.apjtm.2016.10.010] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2016] [Revised: 09/13/2016] [Accepted: 10/10/2016] [Indexed: 11/26/2022] Open
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Guo Y, Wang S, Wang Y, Zhu T. Silymarin improved diet-induced liver damage and insulin resistance by decreasing inflammation in mice. PHARMACEUTICAL BIOLOGY 2016; 54:2995-3000. [PMID: 27387273 DOI: 10.1080/13880209.2016.1199042] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/11/2016] [Revised: 05/18/2016] [Accepted: 06/04/2016] [Indexed: 06/06/2023]
Abstract
CONTEXT Silymarin is the main flavonoid extracted from milk thistle, which has been used to treat liver diseases. OBJECTIVE The in vivo effect of silymarin on HFD-induced insulin resistance and fatty liver in mice was studied. MATERIALS AND METHODS Male C57BL/6 mice were fed with high-fat diet (HFD) to induce obesity and insulin resistance and treated with 30, 60 mg/kg silymarin for 18 days. Food intake, body weight and the content/histology of epididymal fat and liver tissue were examined; the content of lipids, AST, ALT and inflammatory cytokines in serum were estimated. RESULTS Administration of silymarin caused bodyweight loss in diet induced obesity (DIO) mice (HFD group: 47.7 g, 60 mg/kg group: 43.0 g) while the food intake remain unchanged. Silymarin (60 mg/kg) significantly reduced the epididymal fat mass (from 1.75 g to 1.12 g). Elevated plasma lipids (TC 6.1 mM, TG 1.3 mM, LDL 1.2 mM) in DIO mice were all suppressed by silymarin (TC 4.5 mM, TG 0.89 mM, LDL 0.9 mM), as well as insulin (5.1 ng/ml in HFD group to 2.0 ng/ml (60 mg/kg silymarin). Examination of cytokine levels (TNF-α, IL-1β and IL-6) in each group proved that silymarin treatment significantly decreased inflammation in DIO mice. Finally, silymarin effectively protected liver from HFD-induced injury as evidenced by decreasing histological damage and reducing ALT and AST levels, as follows: ALT; 47.4 U/L in HFD group to 28.4 U/L (60 mg/kg silymarin); AST; 150.1 U/L in HFD group to 88.1 U/L (60 mg/kg silymarin) in serum. DISCUSSION AND CONCLUSION Our results suggested that silymarin-induced alleviation of inflammatory response could be a mechanism responsible for its benefits against liver damage and insulin resistance.
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Affiliation(s)
- Yu Guo
- a Graduate School, Tianjin Medical University , Tianjin , PR China
- b Department of Endocrinology , The Affiliated Hospital of Chinese People's Armed Police Force Medical College , Tianjin , PR China
| | - Suli Wang
- b Department of Endocrinology , The Affiliated Hospital of Chinese People's Armed Police Force Medical College , Tianjin , PR China
| | - Ying Wang
- b Department of Endocrinology , The Affiliated Hospital of Chinese People's Armed Police Force Medical College , Tianjin , PR China
| | - Tiehong Zhu
- a Graduate School, Tianjin Medical University , Tianjin , PR China
- b Department of Endocrinology , The Affiliated Hospital of Chinese People's Armed Police Force Medical College , Tianjin , PR China
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Evans RPT, Mourad MM, Dvorkin L, Bramhall SR. Hepatic and Intra-abdominal Tuberculosis: 2016 Update. Curr Infect Dis Rep 2016; 18:45. [PMID: 27796776 DOI: 10.1007/s11908-016-0546-5] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Mycobacterium tuberculosis (TB) infection affects nearly 10 million people a year and causes 1.5 million deaths. TB is common in the immunosuppressed population with 12 % of all new diagnoses occurring in human immune deficiency virus (HIV)-positive patients. Extra-pulmonary TB occurs in 12 % of patients with active TB infection of which 3.5 % is hepatobiliary and 6-38 % is intra-abdominal. Hepatobiliary and intra-abdominal TB can present with a myriad of non-specific symptoms, and therefore, diagnosis requires a high level of suspicion. Accurate and rapid diagnosis requires a multidisciplinary team (MDT) approach using radiology, interventional radiology, surgery and pathology services. Treatment of TB is predominantly medical, yet surgery plays an important role in managing the complications of hepatobiliary and intra-abdominal TB.
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Affiliation(s)
- Richard P T Evans
- Wye Valley NHS Trust, Department of Surgery, The County Hospital, Union Walk, Hereford, HR1 2ER, UK
| | - Moustafa Mabrouk Mourad
- Wye Valley NHS Trust, Department of Surgery, The County Hospital, Union Walk, Hereford, HR1 2ER, UK
| | - Lee Dvorkin
- North Middlesex University Hospital, London, UK
| | - Simon R Bramhall
- Wye Valley NHS Trust, Department of Surgery, The County Hospital, Union Walk, Hereford, HR1 2ER, UK.
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Stine JG, Lewis JH. Current and future directions in the treatment and prevention of drug-induced liver injury: a systematic review. Expert Rev Gastroenterol Hepatol 2015; 10:517-36. [PMID: 26633044 PMCID: PMC5074808 DOI: 10.1586/17474124.2016.1127756] [Citation(s) in RCA: 69] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
While the pace of discovery of new agents, mechanisms and risk factors involved in drug-induced liver injury (DILI) remains brisk, advances in the treatment of acute DILI seems slow by comparison. In general, the key to treating suspected DILI is to stop using the drug prior to developing irreversible liver failure. However, predicting when to stop is an inexact science, and commonly used ALT monitoring is an ineffective strategy outside of clinical trials. The only specific antidote for acute DILI remains N-acetylcysteine (NAC) for acetaminophen poisoning, although NAC is proving to be beneficial in some cases of non-acetaminophen DILI in adults. Corticosteroids can be effective for DILI associated with autoimmune or systemic hypersensitivity features. Ursodeoxycholic acid, silymarin and glycyrrhizin have been used to treat DILI for decades, but success remains anecdotal. Bile acid washout regimens using cholestyramine appear to be more evidenced based, in particular for leflunomide toxicity. For drug-induced acute liver failure, the use of liver support systems is still investigational in the United States and emergency liver transplant remains limited by its availability. Primary prevention appears to be the key to avoiding DILI and the need for acute treatment. Pharmacogenomics, including human leukocyte antigen genotyping and the discovery of specific DILI biomarkers offers significant promise for the future. This article describes and summarizes the numerous and diverse treatment and prevention modalities that are currently available to manage DILI.
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Affiliation(s)
- Jonathan G. Stine
- University of Virginia Health System, Department of Medicine, Division of Gastroenterology and Hepatology, JPA and Lee Street, MSB 2145, PO Box 800708, Charlottesville VA 22908
| | - James H. Lewis
- Georgetown University Medical Center, Department of Medicine, Division of Gastroenterology and Hepatology, 3800 Reservoir Rd NW, Washington, DC 20007
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