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1
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Gao X, Jin Y, Zhu W, Wu X, Wang J, Guo C. Regulation of Eukaryotic Translation Initiation Factor 4E as a Potential Anticancer Strategy. J Med Chem 2023; 66:12678-12696. [PMID: 37725577 DOI: 10.1021/acs.jmedchem.3c00636] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/21/2023]
Abstract
Eukaryotic translation initiation factors (eIFs) are highly expressed in cancer cells, especially eIF4E, the central regulatory node driving cancer cell growth and a potential target for anticancer drugs. eIF4E-targeting strategies primarily focus on inhibiting eIF4E synthesis, interfering with eIF4E/eIF4G interactions, and targeting eIF4E phosphorylation and peptide inhibitors. Although some small-molecule inhibitors are in clinical trials, no eIF4E inhibitors are available for clinical use. We provide an overview of the regulatory mechanisms of eIF4E and summarize the progress in developing and discovering eIF4E inhibitor strategies. We propose that interference with eIF4E/eIF4G interactions will provide a new perspective for the design of eIF4E inhibitors and may be a preferred strategy.
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Affiliation(s)
- Xintao Gao
- College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao 266042, China
| | - Yonglong Jin
- The Affiliated Hospital of Qingdao University, Qingdao 266000, China
| | - Wenyong Zhu
- Department of Thoracic Surgery, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, 266035, China
| | - Xiaochen Wu
- College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao 266042, China
| | - Jing Wang
- Department of Biology Science and Technology, Baotou Teacher's College, Baotou 014030, China
| | - Chuanlong Guo
- College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao 266042, China
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2
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Mahnam K, Ghobadi Z. Finding a prospective dual-target drug for the treatment of coronavirus disease by theoretical study. J Biomol Struct Dyn 2022; 40:12621-12641. [PMID: 34514953 DOI: 10.1080/07391102.2021.1973910] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Spike protein of coronavirus is a key protein in binding and entrance of virus to the human cell via binding to the receptor-binding domain (RBD) domain of S1 subunit to peptidase domain region of ACE2 receptor. In this study, the possible effect of 24 antiviral drugs on the RBD domain of spike protein was investigated via docking and molecular dynamics simulation for finding a dual-target drug. At first, all drugs were docked to the RBD domain of spike protein, and then all complexes and free RBD domains were separately used for molecular dynamics simulation for 50 ns via amber18 software. The simulation results showed that 10 ligands from 28 ligands were separated from the RBD domain, and among 18 remained ligands, baloxavir marboxil, and danoprevir drugs, besides endonuclease activity and protease inhibitory, can bind to key residues of the RBD domain. Then these drugs have a dual target and should be more effective than current drugs, and experimental studies should be done on baloxavir marboxil and danoprevir as more potential drugs for coronavirus disease Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Karim Mahnam
- Department of Biology, Faculty of Sciences, Shahrekord University, Shahrekord, Iran.,Nanotechnology Research Center, Shahrekord University, Shahrekord, Iran
| | - Zahra Ghobadi
- Department of Biology, Faculty of Sciences, Shahrekord University, Shahrekord, Iran
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3
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Abdullah Al Awadh A. Nucleotide and nucleoside-based drugs: past, present, and future. Saudi J Biol Sci 2022; 29:103481. [PMID: 36389209 PMCID: PMC9641258 DOI: 10.1016/j.sjbs.2022.103481] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Revised: 09/28/2022] [Accepted: 10/20/2022] [Indexed: 11/06/2022] Open
Abstract
Nucleotide and nucleoside-based analogue drugs are widely used for the treatment of both acute and chronic viral infections. These drugs inhibit viral replication due to one or more distinct mechanisms. It modifies the virus's genetic structure by reducing viral capacity in every replication cycle. Their clinical success has shown strong effectiveness against several viruses, including ebolavirus, hepatitis C virus, HIV, MERS, SARS-Cov, and the most recent emergent SARS-Cov2. In this review, seven different types of inhibitors have been selected that show broad-spectrum activity against RNA viruses. A detailed overview and mechanism of actionof both analogues are given, and the clinical perspectives are discussed. These inhibitors incorporated the novel SARS-CoV-2 RdRp, further terminating the polymerase activity with variable efficacy. The recent study provides a molecular basis for the inhibitory activity of virus RdRp using nucleotide and nucleoside analogues inhibitors. Furthermore, to identify those drugs that need more research and development to combat novel infections. Consequently, there is a pressing need to focus on present drugs by establishing their cell cultures. If their potencies were evidenced, then they would be explored in the future as potential therapeutics for novel outbreaks.
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Gangadharan S, Ambrose JM, Rajajagadeesan A, Kullappan M, Patil S, Gandhamaneni SH, Veeraraghavan VP, Nakkella AK, Agarwal A, Jayaraman S, Surapaneni KM. Repurposing of potential antiviral drugs against RNA-dependent RNA polymerase of SARS-CoV-2 by computational approach. J Infect Public Health 2022; 15:1180-1191. [PMID: 36240528 PMCID: PMC9514006 DOI: 10.1016/j.jiph.2022.09.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Revised: 09/16/2022] [Accepted: 09/20/2022] [Indexed: 01/18/2023] Open
Abstract
The high incidences of COVID-19 cases are believed to be associated with high transmissibility rates, which emphasizes the need for the discovery of evidence-based antiviral therapies for curing the disease. The rationale of repurposing existing classes of antiviral small molecule therapeutics against SARS-CoV-2 infection has been expected to accelerate the tedious and expensive drug development process. While Remdesivir has been recently approved to be the first treatment option for specific groups of COVID-19 patients, combinatory therapy with potential antiviral drugs may be necessary to enhance the efficacy in different populations. Hence, a comprehensive list of investigational antimicrobial drug compounds such as Favipiravir, Fidaxomicin, Galidesivir, GC376, Ribavirin, Rifabutin, and Umifenovir were computationally evaluated in this study. We performed in silico docking and molecular dynamics simulation on the selected small molecules against RNA-dependent RNA polymerase, which is one of the key target proteins of SARS-CoV-2, using AutoDock and GROMACS. Interestingly, our results revealed that the macrocyclic antibiotic, Fidaxomicin, possesses the highest binding affinity with the lowest energy value of -8.97 kcal/mol binding to the same active sites of RdRp. GC376, Rifabutin, Umifenovir and Remdesivir were identified as the next best compounds. Therefore, the above-mentioned compounds could be considered good leads for further preclinical and clinical experimentations as potentially efficient antiviral inhibitors for combination therapies against SARS-CoV-2.
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Affiliation(s)
- Sivakumar Gangadharan
- Department of Chemistry, Panimalar Engineering College, Varadharajapuram, Poonamallee, Chennai 600123, Tamil Nadu, India.
| | - Jenifer Mallavarpu Ambrose
- Department of Research, Panimalar Medical College Hospital & Research Institute, Varadharajapuram, Chennai 600123, Tamil Nadu, India.
| | - Anusha Rajajagadeesan
- Department of Biochemistry, Panimalar Medical College Hospital & Research Institute, Varadharajapuram, Chennai 600123, Tamil Nadu, India.
| | - Malathi Kullappan
- Department of Research, Panimalar Medical College Hospital & Research Institute, Varadharajapuram, Chennai 600123, Tamil Nadu, India.
| | - Shankargouda Patil
- College of Dental Medicine, Roseman University of Health Sciences, South Jordan, UTAH-84095, USA; Centre of Molecular Medicine and Diagnostics ( COMManD), Saveetha Dental College & Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai 600077, India.
| | - Sri Harshini Gandhamaneni
- Department of General Medicine, Panimalar Medical College Hospital & Research Institute, Varadharajapuram, Chennai 600123, Tamil Nadu, India.
| | - Vishnu Priya Veeraraghavan
- Centre of Molecular Medicine and Diagnostics ( COMManD), Saveetha Dental College & Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai 600077, India.
| | - Aruna Kumari Nakkella
- Department of Engineering Chemistry, Dr B R Ambedkar University, Etcherla, Srikakulam 532410, Andhra Pradesh, India.
| | - Alok Agarwal
- Department of Chemistry, Chinmaya Degree College, BHEL, Haridwar 249403, Uttarakhand, India.
| | - Selvaraj Jayaraman
- Centre of Molecular Medicine and Diagnostics ( COMManD), Saveetha Dental College & Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai 600077, India.
| | - Krishna Mohan Surapaneni
- Departments of Biochemistry, Molecular Virology, Research, Clinical Skills & Simulation, Panimalar Medical College Hospital & Research Institute, Varadharajapuram, Poonamallee, Chennai 600123, Tamil Nadu, India.
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Cajazeiro DC, Toledo PPM, de Sousa NF, Scotti MT, Reimão JQ. Drug Repurposing Based on Protozoan Proteome: In Vitro Evaluation of In Silico Screened Compounds against Toxoplasma gondii. Pharmaceutics 2022; 14:1634. [PMID: 36015260 PMCID: PMC9414507 DOI: 10.3390/pharmaceutics14081634] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 08/01/2022] [Accepted: 08/02/2022] [Indexed: 11/22/2022] Open
Abstract
Toxoplasma gondii is a protozoan that infects up to a third of the world's population. This parasite can cause serious problems, especially if a woman is infected during pregnancy, when toxoplasmosis can cause miscarriage, or serious complications to the baby, or in an immunocompromised person, when the infection can possibly affect the patient's eyes or brain. To identify potential drug candidates that could counter toxoplasmosis, we selected 13 compounds which were pre-screened in silico based on the proteome of T. gondii to be evaluated in vitro against the parasite in a cell-based assay. Among the selected compounds, three demonstrated in vitro anti-T. gondii activity in the nanomolar range (almitrine, bortezomib, and fludarabine), and ten compounds demonstrated anti-T. gondii activity in the micromolar range (digitoxin, digoxin, doxorubicin, fusidic acid, levofloxacin, lomefloxacin, mycophenolic acid, ribavirin, trimethoprim, and valproic acid). Almitrine demonstrated a Selectivity Index (provided by the ratio between the Half Cytotoxic Concentration against human foreskin fibroblasts and the Half Effective Concentration against T. gondii tachyzoites) that was higher than 47, whilst being considered a lead compound against T. gondii. Almitrine showed interactions with the Na+/K+ ATPase transporter for Homo sapiens and Mus musculus, indicating a possible mechanism of action of this compound.
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Affiliation(s)
- Débora Chaves Cajazeiro
- Laboratory of Preclinical Assays and Research of Alternative Sources of Innovative Therapy for Toxoplasmosis and Other Sicknesses (PARASITTOS), Departamento de Morfologia e Patologia Básica, Faculdade de Medicina de Jundiaí, Jundiaí 13202-550, Brazil
| | - Paula Pereira Marques Toledo
- Laboratory of Preclinical Assays and Research of Alternative Sources of Innovative Therapy for Toxoplasmosis and Other Sicknesses (PARASITTOS), Departamento de Morfologia e Patologia Básica, Faculdade de Medicina de Jundiaí, Jundiaí 13202-550, Brazil
| | - Natália Ferreira de Sousa
- Programa de Pós-graduação em Produtos Naturais e Sintéticos Bioativos (PgPNSB), Instituto de Pesquisa em Fármacos e Medicamentos (IPeFarM), Universidade Federal da Paraíba, Campus I, Cidade Universitária, João Pessoa 58051-900, Brazil
| | - Marcus Tullius Scotti
- Programa de Pós-graduação em Produtos Naturais e Sintéticos Bioativos (PgPNSB), Instituto de Pesquisa em Fármacos e Medicamentos (IPeFarM), Universidade Federal da Paraíba, Campus I, Cidade Universitária, João Pessoa 58051-900, Brazil
| | - Juliana Quero Reimão
- Laboratory of Preclinical Assays and Research of Alternative Sources of Innovative Therapy for Toxoplasmosis and Other Sicknesses (PARASITTOS), Departamento de Morfologia e Patologia Básica, Faculdade de Medicina de Jundiaí, Jundiaí 13202-550, Brazil
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6
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Li TW, Kenney AD, Park JG, Fiches GN, Liu H, Zhou D, Biswas A, Zhao W, Que J, Santoso N, Martinez-Sobrido L, Yount JS, Zhu J. SARS-CoV-2 Nsp14 protein associates with IMPDH2 and activates NF-κB signaling. Front Immunol 2022; 13:1007089. [PMID: 36177032 PMCID: PMC9513374 DOI: 10.3389/fimmu.2022.1007089] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Accepted: 08/11/2022] [Indexed: 12/24/2022] Open
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection leads to NF-κB activation and induction of pro-inflammatory cytokines, though the underlying mechanism for this activation is not fully understood. Our results reveal that the SARS-CoV-2 Nsp14 protein contributes to the viral activation of NF-κB signaling. Nsp14 caused the nuclear translocation of NF-κB p65. Nsp14 induced the upregulation of IL-6 and IL-8, which also occurred in SARS-CoV-2 infected cells. IL-8 upregulation was further confirmed in lung tissue samples from COVID-19 patients. A previous proteomic screen identified the putative interaction of Nsp14 with host Inosine-5'-monophosphate dehydrogenase 2 (IMPDH2), which is known to regulate NF-κB signaling. We confirmed the Nsp14-IMPDH2 protein interaction and identified that IMPDH2 knockdown or chemical inhibition using ribavirin (RIB) and mycophenolic acid (MPA) abolishes Nsp14- mediated NF-κB activation and cytokine induction. Furthermore, IMPDH2 inhibitors (RIB, MPA) or NF-κB inhibitors (bortezomib, BAY 11-7082) restricted SARS-CoV-2 infection, indicating that IMPDH2-mediated activation of NF-κB signaling is beneficial to viral replication. Overall, our results identify a novel role of SARS-CoV-2 Nsp14 in inducing NF-κB activation through IMPDH2 to promote viral infection.
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Affiliation(s)
- Tai-Wei Li
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH, United States
| | - Adam D. Kenney
- Department of Microbial Infection and Immunity, The Ohio State University Wexner Medical Center, Columbus, OH, United States
| | - Jun-Gyu Park
- Texas Biomedical Research Institute, San Antonio, TX, United States
| | - Guillaume N. Fiches
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH, United States
| | - Helu Liu
- Department of Medicine, Columbia University Medical Center, New York, NY, United States
| | - Dawei Zhou
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH, United States
| | - Ayan Biswas
- Department of Genetics, The University of Alabama at Birmingham, Birmingham, AL, United States
| | - Weiqiang Zhao
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH, United States
| | - Jianwen Que
- Department of Medicine, Columbia University Medical Center, New York, NY, United States
| | - Netty Santoso
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH, United States
| | | | - Jacob S. Yount
- Department of Microbial Infection and Immunity, The Ohio State University Wexner Medical Center, Columbus, OH, United States
| | - Jian Zhu
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH, United States
- Department of Microbial Infection and Immunity, The Ohio State University Wexner Medical Center, Columbus, OH, United States
- *Correspondence: Jian Zhu,
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7
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Biswas P, Hasan MM, Dey D, Dos Santos Costa AC, Polash SA, Bibi S, Ferdous N, Kaium MA, Rahman MDH, Jeet FK, Papadakos S, Islam K, Uddin MS. Candidate antiviral drugs for COVID-19 and their environmental implications: a comprehensive analysis. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2021; 28:59570-59593. [PMID: 34510341 PMCID: PMC8435122 DOI: 10.1007/s11356-021-16096-3] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Accepted: 08/18/2021] [Indexed: 05/27/2023]
Abstract
Emerging from Wuhan, China, SARS-CoV-2 is the new global threat that killed millions of people, and many are still suffering. This pandemic has not only affected people but also caused economic crisis throughout the world. Researchers have shown good progress in revealing the molecular insights of SARS-CoV-2 pathogenesis and developing vaccines, but effective treatment against SARS-CoV-2-infected patients are yet to be found. Several vaccines are available and used in many countries, while many others are still in clinical or preclinical studies. However, this involves a long-term process, considering the safety procedures and requirements and their long-term protection capacity and in different age groups are still questionable. Therefore, at present, the drug repurposing of the existing therapeutics previously designed against other viral diseases seems to be the only practical approach to mitigate the current situation. The safety of most of these therapeutic agents has already been tested. Recent clinical reports revealed promising therapeutic efficiency of several drugs such as remdesivir, tenofovir disoproxil fumarate, azithromycin, lopinavir/ritonavir, chloroquine, baricitinib, and cepharanthine. Besides, plasma therapies were used to treat patients and prevent fatal outcomes. Thus, in this article, we have summarized the epidemiological and clinical data from several clinical trials conducted since the beginning of the pandemic, emphasizing the efficiency of the known agents against SARS-CoV-2 and their harmful side effects on the human body as well as their environmental implications. This review shows a clear overview of the current pharmaceutical perspective on COVID-19 treatment.
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Affiliation(s)
- Partha Biswas
- Department of Genetic Engineering and Biotechnology, Faculty of Biological Science and Technology, Jashore University of Science and Technology, Jashore, 7408, Bangladesh
| | - Mohammad Mehedi Hasan
- Department of Biochemistry and Molecular Biology, Faculty of Life Science, Mawlana Bhashani Science and Technology University, Tangail, 1902, Bangladesh
| | - Dipta Dey
- Department of Biochemistry and Molecular Biology, Faculty of Life Science, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj, 8100, Bangladesh
| | | | | | - Shabana Bibi
- Yunnan Herbal Laboratory, School of Ecology and Environmental Sciences, Yunnan University, Kunming, 650091, Yunnan, China
| | - Nadim Ferdous
- Department of Biotechnology and Genetic Engineering, Faculty of Life Science, Mawlana Bhashani Science and Technology University, Tangail, 1902, Bangladesh
| | - Md Abu Kaium
- Department of Genetic Engineering and Biotechnology, Faculty of Biological Science and Technology, Jashore University of Science and Technology, Jashore, 7408, Bangladesh
| | - M D Hasanur Rahman
- Department of Biotechnology and Genetic Engineering, Faculty of Life Science, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj, 8100, Bangladesh
| | - Fardin Kamal Jeet
- Biotechnology and Genetic Engineering Discipline, Khulna University, Khulna, Bangladesh
| | - Stavros Papadakos
- First Department of Pathology, School of Medicine, National and Kapodistrian University of Athens (NKUA), Athens, Greece
| | - Khairul Islam
- Department of Biochemistry and Molecular Biology, Faculty of Life Science, Mawlana Bhashani Science and Technology University, Tangail, 1902, Bangladesh
| | - Md Sahab Uddin
- Department of Pharmacy, Southeast University, Dhaka, Bangladesh.
- Pharmakon Neuroscience Research Network, Dhaka, Bangladesh.
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Sivandzadeh GR, Askari H, Safarpour AR, Ejtehadi F, Raeis-Abdollahi E, Vaez Lari A, Abazari MF, Tarkesh F, Bagheri Lankarani K. COVID-19 infection and liver injury: Clinical features, biomarkers, potential mechanisms, treatment, and management challenges. World J Clin Cases 2021; 9:6178-6200. [PMID: 34434987 PMCID: PMC8362548 DOI: 10.12998/wjcc.v9.i22.6178] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Revised: 05/07/2021] [Accepted: 06/25/2021] [Indexed: 02/06/2023] Open
Abstract
It is hypothesized that liver impairment caused by coronavirus disease 2019 (COVID-19) infection might play a central role in severe clinical presentations. Liver injury is closely associated with severe disease and, even with antiviral drugs, have a poor prognosis in COVID-19 patients. In addition to the common hepatobiliary disorders caused by COVID-19, patients with pre-existing liver diseases demand special considerations during the current pandemic. Thus, it is vital that upon clinical presentation, patients with concurrent pre-existing liver disease associated with metabolic dysfunction and COVID-19 be managed properly to prevent liver failure. Careful monitoring and early detection of liver damage through biomarkers after hospitalization for COVID-19 is underscored in all cases, particularly in those with pre-existing metabolic liver injury. The purpose of this study was to determine most recent evidence regarding causality, potential risk factors, and challenges, therapeutic options, and management of COVID-19 infection in vulnerable patients with pre-existing liver injury. This review aims to highlight the current frontier of COVID-19 infection and liver injury and the direction of liver injury in these patients.
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Affiliation(s)
- Gholam Reza Sivandzadeh
- Gastroenterohepatology Research Center, Shiraz University of Medical Sciences, Shiraz 7193635899, Iran
| | - Hassan Askari
- Gastroenterohepatology Research Center, Shiraz University of Medical Sciences, Shiraz 7193635899, Iran
| | - Ali Reza Safarpour
- Gastroenterohepatology Research Center, Shiraz University of Medical Sciences, Shiraz 7193635899, Iran
| | - Fardad Ejtehadi
- Gastroenterohepatology Research Center, Shiraz University of Medical Sciences, Shiraz 7193635899, Iran
| | - Ehsan Raeis-Abdollahi
- Department of Medical Sciences, Qom Medical Branch, Islamic Azad University, Qom 1417613151, Iran
| | - Armaghan Vaez Lari
- Department of Physiology, School of Medicine, Ahvaz Jundishapur University of Medical Science, Ahvaz 6135715794, Iran
| | - Mohammad Foad Abazari
- Research Center for Clinical Virology, Tehran University of Medical Sciences, Tehran 1417653761, Iran
| | - Firoozeh Tarkesh
- Gastroenterohepatology Research Center, Shiraz University of Medical Sciences, Shiraz 7193635899, Iran
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9
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Repurposing of Antimicrobial Agents for Cancer Therapy: What Do We Know? Cancers (Basel) 2021; 13:cancers13133193. [PMID: 34206772 PMCID: PMC8269327 DOI: 10.3390/cancers13133193] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Revised: 06/23/2021] [Accepted: 06/24/2021] [Indexed: 02/07/2023] Open
Abstract
The substantial costs of clinical trials, the lengthy timelines of new drug discovery and development, along the high attrition rates underscore the need for alternative strategies for finding quickly suitable therapeutics agents. Given that most approved drugs possess more than one target tightly linked to other diseases, it encourages promptly testing these drugs in patients. Over the past decades, this has led to considerable attention for drug repurposing, which relies on identifying new uses for approved or investigational drugs outside the scope of the original medical indication. The known safety of approved drugs minimizes the possibility of failure for adverse toxicology, making them attractive de-risked compounds for new applications with potentially lower overall development costs and shorter development timelines. This latter case is an exciting opportunity, specifically in oncology, due to increased resistance towards the current therapies. Indeed, a large body of evidence shows that a wealth of non-cancer drugs has beneficial effects against cancer. Interestingly, 335 drugs are currently being evaluated in different clinical trials for their potential activities against various cancers (Redo database). This review aims to provide an extensive discussion about the anti-cancer activities exerted by antimicrobial agents and presents information about their mechanism(s) of action and stage of development/evaluation.
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10
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Li T, Kenney AD, Liu H, Fiches GN, Zhou D, Biswas A, Que J, Santoso N, Yount JS, Zhu J. SARS-CoV-2 Nsp14 activates NF-κB signaling and induces IL-8 upregulation. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2021:2021.05.26.445787. [PMID: 34075374 PMCID: PMC8168382 DOI: 10.1101/2021.05.26.445787] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection leads to NF-κB activation and induction of pro-inflammatory cytokines, though the underlying mechanism for this activation is not fully understood. Our results reveal that the SARS-CoV-2 Nsp14 protein contributes to the viral activation of NF-κB signaling. Nsp14 caused the nuclear translocation of NF-κB p65. Nsp14 induced the upregulation of IL-6 and IL-8, which also occurred in SARS-CoV-2 infected cells. IL-8 upregulation was further confirmed in lung tissue samples from COVID-19 patients. A previous proteomic screen identified the putative interaction of Nsp14 with host Inosine-5'-monophosphate dehydrogenase 2 (IMPDH2) protein, which is known to regulate NF-κB signaling. We confirmed the Nsp14-IMPDH2 protein interaction and found that IMPDH2 knockdown or chemical inhibition using ribavirin (RIB) and mycophenolic acid (MPA) abolishes Nsp14-mediated NF-κB activation and cytokine induction. Furthermore, IMDPH2 inhibitors (RIB, MPA) efficiently blocked SARS-CoV-2 infection, indicating that IMDPH2, and possibly NF-κB signaling, is beneficial to viral replication. Overall, our results identify a novel role of SARS-CoV-2 Nsp14 in causing the activation of NF-κB.
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Affiliation(s)
- Taiwei Li
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
| | - Adam D. Kenney
- Department of Microbial Infection and Immunity, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
| | - Helu Liu
- Department of Medicine, Columbia University Medical Center, New York, NY 10032, USA
| | - Guillaume N. Fiches
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
| | - Dawei Zhou
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
| | - Ayan Biswas
- Department of Genetics, The University of Alabama at Birmingham, Birmingham, AL 35233, USA
| | - Jianwen Que
- Department of Medicine, Columbia University Medical Center, New York, NY 10032, USA
| | - Netty Santoso
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
| | - Jacob S. Yount
- Department of Microbial Infection and Immunity, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
| | - Jian Zhu
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
- Department of Microbial Infection and Immunity, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
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11
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Romagnoli A, Maracci C, D’Agostino M, Teana AL, Marino DD. Targeting mTOR and eIF4E: a feasible scenario in ovarian cancer therapy. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2021; 4:596-606. [PMID: 35582305 PMCID: PMC9094073 DOI: 10.20517/cdr.2021.20] [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: 03/03/2021] [Revised: 04/22/2021] [Accepted: 04/27/2021] [Indexed: 11/16/2022]
Abstract
Ovarian carcinoma is one of the most common causes for cancer death in women; lack of early diagnosis and acquired resistance to platinum-based chemotherapy account for its poor prognosis and high mortality rate. As with other cancer types, ovarian cancer is characterized by dysregulated signaling pathways and protein synthesis, which together contribute to rapid cellular growth and invasiveness. The mechanistic/mammalian target of rapamycin (mTOR) pathway represents the core of different signaling pathways regulating a number of essential steps in the cell, among which protein synthesis and the eukaryotic initiation factor 4E (eIF4E), the mRNA cap binding protein, is one of its downstream effectors. eIF4E is a limiting factor in translation initiation and its overexpression is a hallmark in many cancers. Because its action is regulated by a number of factors that compete for the same binding site, eIF4E is an ideal target for developing novel antineoplastic drugs. Several inhibitors targeting the mTOR signaling pathway have been designed thus far, however most of these molecules show poor stability and high toxicity in vivo. This minireview explores the possibility of targeting mTOR and eIF4E proteins, thus impacting on translation initiation in ovarian cancer, describing the most promising experimental strategies and specific inhibitors that have been shown to have an effect on other kinds of cancers.
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Affiliation(s)
- Alice Romagnoli
- Department of Life and Environmental Sciences, Polytechnic University of Marche, Ancona 60131, Italy
- New York-Marche Structural Biology Center (NY-MaSBiC), Polytechnic University of Marche, Ancona 60131, Italy
| | - Cristina Maracci
- Department of Life and Environmental Sciences, Polytechnic University of Marche, Ancona 60131, Italy
| | - Mattia D’Agostino
- Department of Life and Environmental Sciences, Polytechnic University of Marche, Ancona 60131, Italy
| | - Anna La Teana
- Department of Life and Environmental Sciences, Polytechnic University of Marche, Ancona 60131, Italy
- New York-Marche Structural Biology Center (NY-MaSBiC), Polytechnic University of Marche, Ancona 60131, Italy
| | - Daniele Di Marino
- Department of Life and Environmental Sciences, Polytechnic University of Marche, Ancona 60131, Italy
- New York-Marche Structural Biology Center (NY-MaSBiC), Polytechnic University of Marche, Ancona 60131, Italy
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12
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Hasan MK, Kamruzzaman M, Bin Manjur OH, Mahmud A, Hussain N, Alam Mondal MS, Hosen MI, Bello M, Rahman A. Structural analogues of existing anti-viral drugs inhibit SARS-CoV-2 RNA dependent RNA polymerase: A computational hierarchical investigation. Heliyon 2021; 7:e06435. [PMID: 33693066 PMCID: PMC7934700 DOI: 10.1016/j.heliyon.2021.e06435] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2020] [Revised: 02/16/2021] [Accepted: 03/03/2021] [Indexed: 01/18/2023] Open
Abstract
The Coronavirus Disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) became a pandemic, resulting in an exponentially increased mortality globally and scientists all over the world are struggling to find suitable solutions to combat it. Multiple repurposed drugs have already been in several clinical trials or recently completed. However, none of them shows any promising effect in combating COVID-19. Therefore, developing an effective drug is an unmet global need. RdRp (RNA dependent RNA polymerase) plays a pivotal role in viral replication. Therefore, it is considered as a prime target of drugs that may treat COVID-19. In this study, we have screened a library of compounds, containing approved RdRp inhibitor drugs that were or in use to treat other viruses (favipiravir, sofosbuvir, ribavirin, lopinavir, tenofovir, ritonavir, galidesivir and remdesivir) and their structural analogues, in order to identify potential inhibitors of SARS-CoV-2 RdRp. Extensive screening, molecular docking and molecular dynamics show that five structural analogues have notable inhibitory effects against RdRp of SARS-CoV-2. Importantly, comparative protein-antagonists interaction revealed that these compounds fit well in the pocket of RdRp. ADMET analysis of these compounds suggests their potency as drug candidates. Our identified compounds may serve as potential therapeutics for COVID-19.
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Affiliation(s)
- Md. Kamrul Hasan
- Department of Biochemistry and Molecular Biology, Tejgaon College, National University, Gazipur 1704, Bangladesh
| | - Mohammad Kamruzzaman
- Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka 1000, Bangladesh
| | - Omar Hamza Bin Manjur
- Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka 1000, Bangladesh
| | - Araf Mahmud
- Department of Genetic Engineering and Biotechnology, Shahjalal University of Science and Technology, Sylhet, 3114, Bangladesh
| | - Nazmul Hussain
- Department of Biochemistry and Molecular Biology, Tejgaon College, National University, Gazipur 1704, Bangladesh
| | | | - Md. Ismail Hosen
- Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka 1000, Bangladesh
| | - Martiniano Bello
- Laboratorio de Diseño y Desarrollo de Nuevos Fármacos e Innovación Biotécnológica (Laboratory for the Design and Development of New Drugs and Biotechnological Innovation), Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón, Ciudad de México 11340, Mexico
| | - Atiqur Rahman
- Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka 1000, Bangladesh
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13
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Liu XH, Zhang X, Lu ZH, Zhu YS, Wang T. Potential molecular targets of nonstructural proteins for the development of antiviral drugs against SARS-CoV-2 infection. Biomed Pharmacother 2020; 133:111035. [PMID: 33254013 PMCID: PMC7671653 DOI: 10.1016/j.biopha.2020.111035] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Revised: 11/10/2020] [Accepted: 11/15/2020] [Indexed: 02/08/2023] Open
Abstract
The pandemic of SARS-CoV-2 has posed significant threats to public health worldwide. Target-based drug development is a promising approach against SARS-CoV-2 infection. Nonstructural proteins may play critical roles from drug design perspectives. Insights into NSPs of different viruses could streamline novel drug development. Outbreaks of severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and SARS-CoV-2 have produced high pathogenicity and mortality rates in human populations. However, to meet the increasing demand for treatment of these pathogenic coronaviruses, accelerating novel antiviral drug development as much as possible has become a public concern. Target-based drug development may be a promising approach to achieve this goal. In this review, the relevant features of potential molecular targets in human coronaviruses (HCoVs) are highlighted, including the viral protease, RNA-dependent RNA polymerase, and methyltransferases. Additionally, recent advances in the development of antivirals based on these targets are summarized. This review is expected to provide new insights and potential strategies for the development of novel antiviral drugs to treat SARS-CoV-2 infection.
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Affiliation(s)
- Xiao-Huan Liu
- School of Biological Science, Jining Medical University, Jining, China
| | - Xiao Zhang
- School of Biological Science, Jining Medical University, Jining, China
| | - Zhen-Hua Lu
- College of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310027, China
| | - You-Shuang Zhu
- School of Biological Science, Jining Medical University, Jining, China
| | - Tao Wang
- School of Biological Science, Jining Medical University, Jining, China.
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14
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Jiang SL, Mo JL, Peng J, Lei L, Yin JY, Zhou HH, Liu ZQ, Hong WX. Targeting translation regulators improves cancer therapy. Genomics 2020; 113:1247-1256. [PMID: 33189778 DOI: 10.1016/j.ygeno.2020.11.011] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Revised: 10/14/2020] [Accepted: 11/11/2020] [Indexed: 02/07/2023]
Abstract
Deregulation of protein synthesis may be involved in multiple aspects of cancer, such as gene expression, signal transduction and drive specific cell biological responses, resulting in promoting cancer growth, invasion and metastasis. Study the molecular mechanisms about translational control may help us to find more effective anti-cancer drugs and develop novel therapeutic opportunities. Recently, the researchers had focused on targeting translational machinery to overcome cancer, and various small molecular inhibitors targeting translation factors or pathways have been tested in clinical trials and exhibited improving outcomes in several cancer types. There is no doubt that an insight into the class of translation regulation protein would provide new target for pharmacologic intervention and further provide opportunities to develop novel anti-tumor therapeutic interventions. In this review, we summarized the developments of translational control in cancer survival and progression et al, and highlighted the therapeutic approach targeted translation regulation to overcome the cancer.
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Affiliation(s)
- Shi-Long Jiang
- Department of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, and National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, PR China; Institute of Clinical Pharmacology, Engineering Research Center for applied Technology of Pharmacogenomics of Ministry of Education, Central South University, Changsha 410078, PR China
| | - Jun-Luan Mo
- Department of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, and National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, PR China; Institute of Clinical Pharmacology, Engineering Research Center for applied Technology of Pharmacogenomics of Ministry of Education, Central South University, Changsha 410078, PR China; Shenzhen Center for Chronic Disease Control and Prevention, Shenzhen 518020, PR China
| | - Ji Peng
- Shenzhen Center for Chronic Disease Control and Prevention, Shenzhen 518020, PR China
| | - Lin Lei
- Shenzhen Center for Chronic Disease Control and Prevention, Shenzhen 518020, PR China
| | - Ji-Ye Yin
- Department of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, and National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, PR China; Institute of Clinical Pharmacology, Engineering Research Center for applied Technology of Pharmacogenomics of Ministry of Education, Central South University, Changsha 410078, PR China
| | - Hong-Hao Zhou
- Department of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, and National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, PR China; Institute of Clinical Pharmacology, Engineering Research Center for applied Technology of Pharmacogenomics of Ministry of Education, Central South University, Changsha 410078, PR China
| | - Zhao-Qian Liu
- Department of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, and National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, PR China; Institute of Clinical Pharmacology, Engineering Research Center for applied Technology of Pharmacogenomics of Ministry of Education, Central South University, Changsha 410078, PR China.
| | - Wen-Xu Hong
- Shenzhen Center for Chronic Disease Control and Prevention, Shenzhen 518020, PR China.
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15
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Tate PM, Mastrodomenico V, Mounce BC. Ribavirin Induces Polyamine Depletion via Nucleotide Depletion to Limit Virus Replication. Cell Rep 2020; 28:2620-2633.e4. [PMID: 31484073 DOI: 10.1016/j.celrep.2019.07.099] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2019] [Revised: 06/24/2019] [Accepted: 07/26/2019] [Indexed: 11/16/2022] Open
Abstract
Common antivirals include nucleoside or nucleotide analogs with base prodrugs. The antiviral ribavirin, a US Food and Drug Administration (FDA)-approved nucleoside antimetabolite, halts guanine production, mutagenizes viral genomes, and activates interferon signaling. Here, we find that ribavirin induces spermidine-spermine N1-acetyltransferase (SAT1), a polyamine catabolic enzyme. Polyamines are small, positively charged molecules involved in cellular functions such as transcription and translation. Previous work showed that SAT1 activation and polyamine depletion interfere with RNA virus replication. We show ribavirin depletes polyamines via SAT1, in conjunction with its known mechanisms. SAT1 transcripts, protein, and activity are induced in a dose-dependent manner, which depletes polyamine levels and reduces viral titers. Inhibition of SAT1 activity, pharmacologically or genetically, reduces ribavirin's effectiveness against three virus infection models. Additionally, ribavirin-mediated polyamine depletion results from nucleotide pool depletion. These data demonstrate another mechanism of ribavirin that inform its clinical effectiveness, which may provide insight for improved therapies.
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Affiliation(s)
- Patrick M Tate
- Department of Microbiology and Immunology, Loyola University Chicago, Maywood, IL 60153, USA
| | - Vincent Mastrodomenico
- Department of Microbiology and Immunology, Loyola University Chicago, Maywood, IL 60153, USA
| | - Bryan C Mounce
- Department of Microbiology and Immunology, Loyola University Chicago, Maywood, IL 60153, USA.
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16
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Mishra RK, Datey A, Hussain T. mRNA Recruiting eIF4 Factors Involved in Protein Synthesis and Its Regulation. Biochemistry 2019; 59:34-46. [DOI: 10.1021/acs.biochem.9b00788] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Affiliation(s)
- Rishi Kumar Mishra
- Department of Molecular Reproduction, Development and Genetics, Division of Biological Sciences, Indian Institute of Science, Bangalore 560012, India
| | - Ayushi Datey
- Department of Molecular Reproduction, Development and Genetics, Division of Biological Sciences, Indian Institute of Science, Bangalore 560012, India
| | - Tanweer Hussain
- Department of Molecular Reproduction, Development and Genetics, Division of Biological Sciences, Indian Institute of Science, Bangalore 560012, India
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17
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Abdelkawy KS, El-Haggar SM, Ziada DH, Ebaid NF, El-Magd MA, Elbarbry FA. The effect of genetic variations on ribavirin pharmacokinetics and treatment response in HCV-4 Egyptian patients receiving sofosbuvir/daclatasvir and ribavirin. Biomed Pharmacother 2019; 121:109657. [PMID: 31810127 DOI: 10.1016/j.biopha.2019.109657] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2019] [Revised: 11/04/2019] [Accepted: 11/06/2019] [Indexed: 12/21/2022] Open
Abstract
PURPOSE This study aimed to investigate the effect of single nucleotide polymorphisms (SNPs) of genes involved in ribavirin (RBV) transport (SLC28A2 gene, ABCB1 gene and ABCB11 gene) on the clinical outcome and pharmacokinetics of ribavirin in HCV- 4 Egyptian patients. METHOD 100 patients treated with sofosbuvir/daclatasvir and ribavirin for 12 weeks. The SNP genotyping was performed by real-time PCR using high resolution melting analysis. Ribavirin plasma trough concentrations were determined at week 4 of therapy using a liquid chromatography/tandem mass spectrometry (LC-MS/MS). For clinical outcomes, sustained virological response (SVR), liver function tests (ALT and AST), total bilirubin, albumin, serum creatinine, hemoglobin, leukocyte count, and platelet count were measured. RESULTS Concerning RBV pharmacokinetics, ABCB1 2677 G > T SNP and ABCB11 1331 T > C SNP were statistically associated with RBV Ctrough levels after 4 weeks of therapy. ABCB11 1331 T > C SNP revealed significant association with clinical outcomes (SVR). SLC28A2-146 A > T SNP has not showed any statistically significant association with RBV plasma levels or response. CONCLUSION SNP genotyping for ABCB1 and ABCB11 genes can help in better personalized medicine for maximizing response for ribavirin as explored by the significant association between polymorphism in ABCB1 and ABCB11 genes and ribavirin pharmacokinetics and the significant association of ABCB11 1331 T > C SNP with clinical response.
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Affiliation(s)
- K S Abdelkawy
- Clinical Pharmacy, Faculty of Pharmacy, Kafrelsheikh University, Egypt.
| | - S M El-Haggar
- Clinical Pharmacy, Faculty of Pharmacy, Tanta University, Egypt.
| | - D H Ziada
- Tropical Medicine and Infectious Diseases, Faculty of Medicine, Tanta University, Egypt.
| | - N F Ebaid
- Clinical Pharmacy, Faculty of Pharmacy, Kafrelsheikh University, Egypt.
| | - M A El-Magd
- Anatomy and Embryology, Faculty of Veterinary Medicine, Kafrelsheikh University, Egypt.
| | - F A Elbarbry
- Pacific University Oregon School of Pharmacy, 222 SE 8thAve., Hillsboro, OR, 97123, USA.
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18
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De Winter BCM, Hesselink DA, Kamar N. Dosing ribavirin in hepatitis E-infected solid organ transplant recipients. Pharmacol Res 2018; 130:308-315. [PMID: 29499270 DOI: 10.1016/j.phrs.2018.02.030] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2017] [Revised: 02/06/2018] [Accepted: 02/26/2018] [Indexed: 12/22/2022]
Abstract
Hepatitis E virus (HEV) is the most common cause of viral hepatitis worldwide. Genotypes 1 and 2 (GT1 and GT2) are mainly present in developing countries, while GT3 and GT4 are prevalent in developed and high-income countries. In the majority of cases, HEV causes a self-limiting hepatitis. GT3 and GT4 can be responsible for a chronic hepatitis that can lead to cirrhosis in immunocompromized patients, i.e. solid-organ- and stem-cell-transplant-patients, human immunodeficiency virus-infected patients, and patients receiving chemotherapy or immunotherapy. HEV has also been associated with extra-hepatic manifestations such as neurologic disorders (Guillain-Barré Syndrome and neuralgic amyotrophy) and kidney disease. In patients with chronic hepatitis, reduction of immunosuppression, when possible, is the first therapeutic option. In the remaining patients, ribavirin therapy has been shown to very efficient for treating HEV infection leading to a sustained virological response in nearly 80-85% of patients. However, the mechanism of action of ribavirin in this setting is still unknown, as is the impact of HEV RNA polymerase mutations. There are unmet needs with regard to the treatment of chronic HEV with ribavirin. These include the optimal dosing and duration of treatment, and the potential beneficial effects of therapeutic drug monitoring on the virological response and the incidence of side effects. In the present review, we will provide an overview of HEV epidemiology, its mode of transmission and clinical manifestations, as well as its treatment by ribavirin with a focus on the drug's pharmacokinetics and dosing.
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Affiliation(s)
- Brenda C M De Winter
- Department of Hospital Pharmacy, Erasmus MC, University Medical Center Rotterdam, The Netherlands
| | - Dennis A Hesselink
- Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, The Netherlands; Rotterdam Transplant Group, Division of Nephrology and Organ Transplantation, CHU Rangueil, INSERM U1043, IFR-BMT, Université Paul Sabatier, Toulouse, France
| | - Nassim Kamar
- Department of Internal Medicine, Division of Nephrology and Organ Transplantation, CHU Rangueil, INSERM U1043, IFR-BMT, Université Paul Sabatier, Toulouse, France.
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19
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Fouad R, Zachariah K, Khairy M, Khorshied M, Ezzat W, Sheta MM, Heiba A. Single Nucleotide rs760370 Polymorphism at the Main Ribavirin Transporter Gene Detection by PCR-RFLP Assay Compared with the TaqMan Assay and Its Relation to Sustained Virological Response in Chronic HCV Patients Treated with Pegylated Interferon-Ribavirin Therapy. J Interferon Cytokine Res 2018; 37:90-96. [PMID: 28207300 DOI: 10.1089/jir.2016.0099] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Ribavirin clearly plays a role in chronic hepatitis C treatment response. The equilibrative nucleoside transporter-1 codified by SLC29A1 gene has been associated with ribavirin uptake into hepatocytes and erythrocytes. rs760370A>G single nucleotide polymorphism (SNP) at the SLC29A1 gene may have a role in ribavirin-based regimen treatment response. Accuracy of the polymerase-chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay compared with the TaqMan assay for the detection of the SNP rs760370 at the main ribavirin transporter gene and its relation to sustained virological response in chronic hepatitis C virus (HCV) patients treated with pegylated interferon-ribavirin therapy. The study included 100 chronic HCV patients who were treated with pegylated interferon-ribavirin therapy. The patients were categorized according to the treatment response into responders (50 patients) and null responders (50 patients). rs760370 SNP was measured using TaqMan 5-nuclease assay and by the newly developed PCR-based RFLP assay. The overall accuracy of the newly developed PCR-RFLP assay compared with the TaqMan assay for rs760370 polymorphism detection was 100%. Allelic frequencies at rs760370 were as follows: A/A genotype (28%), A/G genotype (58%), and G/G genotype (14%). Treatment response was not significantly related with rs760370 polymorphism (P = 0.5). Ribavirin-induced anemia was good predictor of sustained virological response (P = 0.001), but was not related to rs760370 polymorphism (P = 0.92). PCR-RFLP assay is an accurate, cost-effective method in the detection of rs760370 compared with TaqMan assay. rs760370 SNP cannot serve as predictor of response in chronic HCV patients treated with interferon ribavirin therapy.
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Affiliation(s)
- Rabab Fouad
- 1 Endemic Medicine Department and Hepatology Unit, Faculty of Medicine, Cairo University , Cairo, Egypt
| | - Khaled Zachariah
- 1 Endemic Medicine Department and Hepatology Unit, Faculty of Medicine, Cairo University , Cairo, Egypt
| | - Marwa Khairy
- 1 Endemic Medicine Department and Hepatology Unit, Faculty of Medicine, Cairo University , Cairo, Egypt
| | - Mervat Khorshied
- 2 Clinical and Chemical Pathology Department, Faculty of Medicine, Cairo University , Cairo, Egypt
| | - Wafaa Ezzat
- 3 Topical Medicine Department, National Research Center, Cairo, Egypt
| | - Marwa M Sheta
- 2 Clinical and Chemical Pathology Department, Faculty of Medicine, Cairo University , Cairo, Egypt
| | - Ahmed Heiba
- 3 Topical Medicine Department, National Research Center, Cairo, Egypt
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Carrillo-Bustamante P, Nguyen THT, Oestereich L, Günther S, Guedj J, Graw F. Determining Ribavirin's mechanism of action against Lassa virus infection. Sci Rep 2017; 7:11693. [PMID: 28916737 PMCID: PMC5601963 DOI: 10.1038/s41598-017-10198-0] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2017] [Accepted: 08/04/2017] [Indexed: 12/11/2022] Open
Abstract
Ribavirin is a broad spectrum antiviral which inhibits Lassa virus (LASV) replication in vitro but exhibits a minor effect on viremia in vivo. However, ribavirin significantly improves the disease outcome when administered in combination with sub-optimal doses of favipiravir, a strong antiviral drug. The mechanisms explaining these conflicting findings have not been determined, so far. Here, we used an interdisciplinary approach combining mathematical models and experimental data in LASV-infected mice that were treated with ribavirin alone or in combination with the drug favipiravir to explore different putative mechanisms of action for ribavirin. We test four different hypotheses that have been previously suggested for ribavirin’s mode of action: (i) acting as a mutagen, thereby limiting the infectivity of new virions; (ii) reducing viremia by impairing viral production; (iii) modulating cell damage, i.e., by reducing inflammation, and (iv) enhancing antiviral immunity. Our analysis indicates that enhancement of antiviral immunity, as well as effects on viral production or transmission are unlikely to be ribavirin’s main mechanism mediating its antiviral effectiveness against LASV infection. Instead, the modeled viral kinetics suggest that the main mode of action of ribavirin is to protect infected cells from dying, possibly reducing the inflammatory response.
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Affiliation(s)
- Paola Carrillo-Bustamante
- Center for Modeling and Simulation in the Biosciences (BIOMS), BioQuant-Center, Heidelberg University, Heidelberg, Germany.
| | - Thi Huyen Tram Nguyen
- INSERM, IAME, UMR, 1137, Paris, France.,Université Paris Diderot, IAME, UMR, 1137, Sorbonne Paris Cité, France
| | - Lisa Oestereich
- Bernhard-Nocht-Institute for Tropical Medicine, Hamburg, Germany.,German Center for Infection Research (DZIF), Partner Site Hamburg, Germany
| | - Stephan Günther
- Bernhard-Nocht-Institute for Tropical Medicine, Hamburg, Germany.,German Center for Infection Research (DZIF), Partner Site Hamburg, Germany
| | - Jeremie Guedj
- INSERM, IAME, UMR, 1137, Paris, France.,Université Paris Diderot, IAME, UMR, 1137, Sorbonne Paris Cité, France
| | - Frederik Graw
- Center for Modeling and Simulation in the Biosciences (BIOMS), BioQuant-Center, Heidelberg University, Heidelberg, Germany.
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Abstract
PURPOSE OF REVIEW The current overview will summarize some of the developments in the area of protein translation, including their relation to the therapeutic targeting of prostate cancer. RECENT FINDINGS Translational control, mediated by the rate-limiting eukaryotic translation initiation factor 4E (eIF4E), drives selective translation of several oncogenic proteins, thereby contributing to tumor growth, metastasis, and treatment resistance in various cancers, including prostate cancer. As an essential regulatory hub, several oncogenic hyperactive signaling pathways appear to converge on eIF4E to promote tumorigenesis. Several approaches that target the eIF4E-dependent protein translation network are being actively studied, and it is likely that some may ultimately emerge as promising anticancer therapeutics. SUMMARY An array of inhibitors has shown promise in targeting specific components of the translational machinery in several preclinical models of prostate cancer. It is hoped that some of these approaches may ultimately have relevance in improving the clinical outcomes of patients with advanced prostate cancer.
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Hayes CN, Chayama K. Why highly effective drugs are not enough: the need for an affordable solution to eliminating HCV. Expert Rev Clin Pharmacol 2017; 10:583-594. [PMID: 28374641 DOI: 10.1080/17512433.2017.1313111] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
INTRODUCTION Because of the rapid pace of development of new direct-acting antiviral (DAA) drugs, chronic hepatitis C virus (HCV) infection is now increasingly considered curable. However, the emphasis on DAA therapies disregards key issues related to cost, availability, and antiviral resistance. Areas covered: This perspective provides an overview of current HCV therapies and the development of DAAs, followed by a discussion of the limitations of DAA therapy. A literature search was used to select relevant studies, and a web search for relevant news articles and press releases was conducted. Expert commentary: Despite cure rates exceeding 90%, now is not the time to declare victory against HCV but to reinforce recent progress by addressing the issues of cost and availability as well as by developing strategies to manage antiviral resistance. Future drug development efforts should place greater emphasis on targeting host factors required for HCV replication, for which the barrier to resistance is higher, and effort should continue to develop a vaccine against HCV. Finally, efforts should be made to facilitate large-scale screening in endemic areas to identify and treat patients as early as possible to reduce long-term risks of advanced liver disease and their attendant costs of management.
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Affiliation(s)
- C Nelson Hayes
- a Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences , Hiroshima University , Hiroshima , Japan.,b Liver Research Project Center , Hiroshima University , Hiroshima , Japan
| | - Kazuaki Chayama
- a Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences , Hiroshima University , Hiroshima , Japan.,b Liver Research Project Center , Hiroshima University , Hiroshima , Japan.,c Laboratory for Digestive Diseases, Center for Genomic Medicine , RIKEN , Hiroshima , Japan
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23
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Hayes CN, Imamura M, Chayama K. The practical management of chronic hepatitis C infection in Japan - dual therapy of daclatasvir + asunaprevir. Expert Rev Gastroenterol Hepatol 2017; 11:103-113. [PMID: 27936974 DOI: 10.1080/17474124.2017.1270205] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Without treatment, many of the 200 million people worldwide with chronic hepatitis C virus (HCV) infection will develop cirrhosis or liver cancer. Japan was the first nation to approve an interferon-free therapy for HCV, and sustained viral response (SVR) rates >90% have been achieved with asunaprevir, a protease inhibitor, plus daclatasvir, an inhibitor of the non-structural 5A (NS5A) protein. Areas covered: This review provides an overview of the results from both clinical trials and real world experience with asunaprevir and daclatasvir therapy focused primarily on Japan. A literature search using the keywords 'asunaprevir,' 'daclatasvir,' 'interferon-free therapy,' and 'direct-acting antiviral drugs' was initially used to select relevant literature for inclusion in the review. Expert commentary: While not approved in the United States, dual therapy with asunaprevir plus daclatasvir has already been successfully used in Japan and throughout East Asia to treat many thousands of patients. Pre-existing or treatment-emergent NS5A-Y93 or -L31 resistance-associated variants (RAVs) may lead to viral breakthrough, and alternative therapies should be considered for these patients, but patients who harbor NS5A RAVs only at low frequency are likely to achieve SVR. The therapy has also been shown to be safe and effective with renal dysfunction or liver cirrhosis.
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Affiliation(s)
- C Nelson Hayes
- a Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences , Hiroshima University , Minami-ku , Hiroshima , Japan.,b Liver Research Project Center , Hiroshima University , Hiroshima , Japan
| | - Michio Imamura
- a Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences , Hiroshima University , Minami-ku , Hiroshima , Japan.,b Liver Research Project Center , Hiroshima University , Hiroshima , Japan
| | - Kazuaki Chayama
- a Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences , Hiroshima University , Minami-ku , Hiroshima , Japan.,b Liver Research Project Center , Hiroshima University , Hiroshima , Japan.,c Laboratory for Digestive Diseases , Center for Genomic Medicine, RIKEN , Hiroshima , Japan
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Zeuzem S. Treatment Options in Hepatitis C. DEUTSCHES ARZTEBLATT INTERNATIONAL 2017; 114:11-21. [PMID: 28143635 PMCID: PMC5373481 DOI: 10.3238/arztebl.2017.0011] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/22/2016] [Revised: 08/22/2016] [Accepted: 11/03/2016] [Indexed: 02/06/2023]
Abstract
BACKGROUND Among patients with chronic hepatitis C, 20-30% develop hepatic cirrhosis and its complications within 30 years. The antiviral treatment of hepatitis C, previously interferon-based, has recently become inter - feron-free, with resulting improvements in sustained virological response rates, safety, and tolerability and a shorter duration of treatment. METHODS This review is based on relevant publications retrieved by a selective literature search, and particularly on studies and reviews concerning the course and treatment of hepatitis C. RESULTS The available drugs for interferon-free antiviral treatment of hepatitis C include inhibitors of the RNAdependent RNA polymerase, NS3/4A protease, and NS5A protein of the hepatitis C virus (HCV), and ribavirin. Typically, two specific inhibitors are given in combination; the usual duration of treatment is 12 weeks.The antiviral drugs differ in their genotypic antiviral effectiveness and resistance barriers. The appropriate drug(s) should be chosen in consideration of the patient's hepatic and renal function and potential drug interactions. These drugs are safe and well-tolerated and result in sustained virological response rates between 90% and 100%. CONCLUSION All patients with hepatitis C, whatever their disease stage, can derive a sustained eradication of HCV from a combination of drugs with direct antiviral activity. Viral eradication is associated with a better quality of life and with lower morbidity and mortality.
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Affiliation(s)
- Stefan Zeuzem
- Medical Clinik I, Department of Internal Medicine, J.W. Goethe University Hospital, Frankfurt/Main
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Reuter A, Horie M, Höper D, Ohnemus A, Narr A, Rinder M, Beer M, Staeheli P, Rubbenstroth D. Synergistic antiviral activity of ribavirin and interferon-α against parrot bornaviruses in avian cells. J Gen Virol 2016; 97:2096-2103. [PMID: 27439314 DOI: 10.1099/jgv.0.000555] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Avian bornaviruses are the causative agents of proventricular dilatation disease (PDD), a widely distributed and often fatal disease in captive psittacines. Because neither specific prevention measures nor therapies against PDD and bornavirus infections are currently available, new antiviral strategies are required to improve animal health. We show here that the nucleoside analogue ribavirin inhibited bornavirus activity in a polymerase reconstitution assay and reduced viral load in avian cell lines infected with two different parrot bornaviruses. Furthermore, we observed that ribavirin enhanced type I IFN signalling in avian cells. Combined treatment of avian bornavirus-infected cells with ribavirin and recombinant IFN-α strongly enhanced the antiviral efficiency compared to either drug alone. The combined use of ribavirin and type I IFN might represent a promising new strategy for therapeutic treatment of captive parrots persistently infected with avian bornaviruses.
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Affiliation(s)
- Antje Reuter
- Institute for Virology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Hermann-Herder-Str. 11, D-79104 Freiburg, Germany
| | - Masayuki Horie
- Transboundary Animal Diseases Research Center, Joint Faculty of Veterinary Medicine, Kagoshima University, Kagoshima 890-0065, Japan.,United Graduate School of Veterinary Science, Yamaguchi University, Yamaguchi 753-851, Japan
| | - Dirk Höper
- Institute of Diagnostic Virology, Friedrich-Loeffler-Institute, Südufer 10, D-17493 Greifswald - Insel Riems, Germany
| | - Annette Ohnemus
- Institute for Virology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Hermann-Herder-Str. 11, D-79104 Freiburg, Germany
| | - Andreas Narr
- Institute for Virology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Hermann-Herder-Str. 11, D-79104 Freiburg, Germany
| | - Monika Rinder
- Clinic for Birds, Reptiles, Amphibians and Ornamental Fish, Centre for Clinical Veterinary Medicine, University Ludwig Maximilian Munich, Sonnenstr. 18, D-85764 Oberschleißheim, Germany
| | - Martin Beer
- Institute of Diagnostic Virology, Friedrich-Loeffler-Institute, Südufer 10, D-17493 Greifswald - Insel Riems, Germany
| | - Peter Staeheli
- Institute for Virology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Hermann-Herder-Str. 11, D-79104 Freiburg, Germany
| | - Dennis Rubbenstroth
- Institute for Virology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Hermann-Herder-Str. 11, D-79104 Freiburg, Germany
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Ghoneim RH, Piquette-Miller M. Endotoxin-Mediated Downregulation of Hepatic Drug Transporters in HIV-1 Transgenic Rats. Drug Metab Dispos 2016; 44:709-19. [PMID: 26977098 DOI: 10.1124/dmd.115.067827] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2015] [Accepted: 03/08/2016] [Indexed: 01/06/2023] Open
Abstract
Altered expression of drug transporters and metabolic enzymes is known to occur in infection-induced inflammation. We hypothesize that in human immunodeficiency virus (HIV)-infected individuals, further alteration could occur as a result of augmented inflammation. The HIV-1 transgenic (Tg) rat is used to simulate HIV pathologies associated with the presence of HIV viral proteins. Therefore, the objective of this study was to examine the effect of endotoxin administration on the gene expression of drug transporters in the liver of HIV-Tg rats. Male and female HIV-Tg and wild-type (WT) littermates were injected with 5 mg/kg endotoxin or saline (n= 7-9/group). Eighteen hours later, rats were euthanized and tissues were collected. Quantitative real-time polymerase chain reaction and Western blot analysis were used to measure hepatic gene and protein expression, respectively, and enzyme-linked immunosorbent assay was used to measure serum cytokine levels. Although an augmented inflammatory response was seen in HIV-Tg rats, similar endotoxin- mediated downregulation of Abcb1a, Abcc2, Abcg2, Abcb11, Slco1a1, Slco1a2, Slco1b2, Slc10a1, Slc22a1, Cyp3a2, and Cyp3a9 gene expression was seen in the HIV-Tg and WT groups. A significantly greater endotoxin- mediated downregulation of Ent1/Slc29a1 was seen in female HIV-Tg rats. Basal expression of inflammatory mediators was not altered in the HIV-Tg rat; likewise, the basal expression of most transporters was not significantly different between HIV-Tg and WT rats. Our findings suggest that hepatobiliary clearances of endogenous and exogenous substrates are altered in the HIV-Tg rat after endotoxin exposure. This is of particular importance because HIV-infected individuals frequently present with bacterial or viral infections, which are a potential source for drug-disease interactions.
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Affiliation(s)
- Ragia H Ghoneim
- Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada
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Lu MY, Huang CI, Dai CY, Wang SC, Hsieh MY, Hsieh MH, Liang PC, Lin YH, Hou NJ, Yeh ML, Huang CF, Lin ZY, Chen SC, Huang JF, Chuang WL, Yu ML. Elevated on-treatment levels of serum IFN-gamma is associated with treatment failure of peginterferon plus ribavirin therapy for chronic hepatitis C. Sci Rep 2016; 6:22995. [PMID: 26965318 PMCID: PMC4786849 DOI: 10.1038/srep22995] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2015] [Accepted: 02/22/2016] [Indexed: 02/07/2023] Open
Abstract
Chronic hepatitis C virus (HCV) infection had been associated with cytokine imbalance. Cytokine dynamics in response to peginterferon/ribavirin therapy have an impact on the treatment efficacy for HCV patients. Ninety-two treatment-naive chronic hepatitis C patients were treated with 24 or 48 weeks of peginterferon/ribavirin therapy according to their viral genotypes. Sustained virologic response (SVR) is defined as undetectable HCV RNA throughout a 24-week post-treatment follow-up period. Dynamic serum levels of the following cytokines: (1) Th1-mediated cytokines: IFN-γ, interleukin-2, and TNF-alpha; (2)Th2-mediated cytokines: interleukin-4, interleukin-5, interleukin-6, and interleukin-10 and (3)immuno-modulatory cytokines: interleukin-1β, interleukin-8, and interleukin-12 were determined by Fluorescent Bead immunoassay. Serial dynamic cytokine expression demonstrated that not only elevated IFN-γ concentrations at specific time points but also the total IFN-γ amount was strongly linked to non-response in peginterferon/ribavirin therapy. IFN-γ levels could serve as an independent predictor for SVR analyzed by multivariate logistic regression test. The accuracy of discriminating responders from non-responders was acceptable when IFN-γ cut-off levels were set at 180, 120, and 40 pg/ml at the 4th week, 12th week, and end-of-treatment of therapy, respectively. Elevated on-treatment IFN-γ concentration was significantly associated with treatment failure among interleukin-28B rs8099917TT carriers and those patients failed to achieve rapid virologic response.
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Affiliation(s)
- Ming-Ying Lu
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ching-I Huang
- Department of Internal Medicine, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chia-Yen Dai
- Hepatobiliary Division, Department of Internal Medicine and Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Faculty of Internal Medicine, College of Medicine, and Graduate Institute of Clinical Medicine, and Center for Infectious Disease and Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Shu-Chi Wang
- Hepatobiliary Division, Department of Internal Medicine and Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Department of Preventive Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Ming-Yen Hsieh
- Hepatobiliary Division, Department of Internal Medicine and Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Meng-Hsuan Hsieh
- Faculty of Internal Medicine, College of Medicine, and Graduate Institute of Clinical Medicine, and Center for Infectious Disease and Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Preventive Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Po-Cheng Liang
- Hepatobiliary Division, Department of Internal Medicine and Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Yi-Hung Lin
- Hepatobiliary Division, Department of Internal Medicine and Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Nai-Jen Hou
- Department of Internal Medicine, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ming-Lun Yeh
- Hepatobiliary Division, Department of Internal Medicine and Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Faculty of Internal Medicine, College of Medicine, and Graduate Institute of Clinical Medicine, and Center for Infectious Disease and Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chung-Feng Huang
- Hepatobiliary Division, Department of Internal Medicine and Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Faculty of Internal Medicine, College of Medicine, and Graduate Institute of Clinical Medicine, and Center for Infectious Disease and Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Occupational Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Zu-Yau Lin
- Hepatobiliary Division, Department of Internal Medicine and Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Faculty of Internal Medicine, College of Medicine, and Graduate Institute of Clinical Medicine, and Center for Infectious Disease and Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Shinn-Cherng Chen
- Hepatobiliary Division, Department of Internal Medicine and Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Faculty of Internal Medicine, College of Medicine, and Graduate Institute of Clinical Medicine, and Center for Infectious Disease and Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Jee-Fu Huang
- Hepatobiliary Division, Department of Internal Medicine and Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Faculty of Internal Medicine, College of Medicine, and Graduate Institute of Clinical Medicine, and Center for Infectious Disease and Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Wan-Long Chuang
- Hepatobiliary Division, Department of Internal Medicine and Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Faculty of Internal Medicine, College of Medicine, and Graduate Institute of Clinical Medicine, and Center for Infectious Disease and Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ming-Lung Yu
- Hepatobiliary Division, Department of Internal Medicine and Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Faculty of Internal Medicine, College of Medicine, and Graduate Institute of Clinical Medicine, and Center for Infectious Disease and Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan
- Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan
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Keppeke GD, Calise SJ, Chan EKL, Andrade LEC. Anti-rods/rings autoantibody generation in hepatitis C patients during interferon-α/ribavirin therapy. World J Gastroenterol 2016; 22:1966-1974. [PMID: 26877604 PMCID: PMC4726672 DOI: 10.3748/wjg.v22.i6.1966] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2015] [Revised: 11/04/2015] [Accepted: 11/24/2015] [Indexed: 02/06/2023] Open
Abstract
Chronic inflammation associated with hepatitis C virus (HCV) infection can lead to disabling liver diseases with progression to liver cirrhosis and hepatocellular carcinoma. Despite the recent availability of more effective and less toxic therapeutic options, in most parts of the world the standard treatment consists of a weekly injection of pegylated interferon α (IFN-α) together with a daily dose of ribavirin. HCV patients frequently present circulating non-organ-specific autoantibodies demonstrating a variety of staining patterns in the indirect immunofluorescence assay for antinuclear antibodies (ANA). Between 20% to 40% of HCV patients treated with IFN-α and ribavirin develop autoantibodies showing a peculiar ANA pattern characterized as rods and rings (RR) structures. The aim of this article is to review the recent reports regarding RR structures and anti-rods/rings (anti-RR) autoantibody production by HCV patients after IFN-α/ribavirin treatment. Anti-RR autoantibodies first appear around the sixth month of treatment and reach a plateau around the twelfth month. After treatment completion, anti-RR titers decrease/disappear in half the patients and remain steady in the other half. Some studies have observed a higher frequency of anti-RR antibodies in relapsers, i.e., patients in which circulating virus reappears after initially successful therapy. The main target of anti-RR autoantibodies in HCV patients is inosine-5’-monophosphate dehydrogenase 2 (IMPDH2), the rate-limiting enzyme involved in the guanosine triphosphate biosynthesis pathway. Ribavirin is a direct IMPDH2 inhibitor and is able to induce the formation of RR structures in vitro and in vivo. In conclusion, these observations led to the hypothesis that anti-RR autoantibody production is a human model of immunologic tolerance breakdown that allows us to explore the humoral autoimmune response from the beginning of the putative triggering event: exposure to ribavirin and interferon.
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Abstract
The translation initiation factor eIF4E mediates a rate-limiting process that drives selective translation of many oncongenic proteins such as cyclin D1, survivin and VEGF, thereby contributing to tumour growth, metastasis and therapy resistance. As an essential regulatory hub in cancer signalling network, many oncogenic signalling pathways appear to converge on eIF4E. Therefore, targeting eIF4E-mediated cap-dependent translation is considered a promising anticancer strategy. This paper reviews the strategies that can be used to target eIF4E, highlighting agents that target eIF4E activity at each distinct level.
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Population pharmacokinetic modeling of plasma and intracellular ribavirin concentrations in patients with chronic hepatitis C virus infection. Antimicrob Agents Chemother 2015; 59:2179-88. [PMID: 25645847 DOI: 10.1128/aac.04618-14] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Ribavirin, a guanosine analog, is a broad-spectrum antiviral agent. Ribavirin has been a fundamental component of the treatment of hepatitis C virus (HCV) infection for decades, but there is a very limited understanding of the clinical pharmacology of this drug. Furthermore, it is associated with a major dose-limiting toxicity, hemolytic anemia. Ribavirin undergoes intracellular phosphorylation by host enzymes to ribavirin monophosphate (RMP), ribavirin diphosphate (RDP), and ribavirin triphosphate (RTP). The intracellular forms have been associated with antiviral and toxic effects in vitro, but the kinetics of these phosphorylated moieties have not been fully elucidated in vivo. We developed a model to characterize the plasma pharmacokinetics of ribavirin and the difference between intracellular phosphorylation kinetics in red cells (nonnucleated) and in peripheral blood mononuclear cells (nucleated). A time-independent two-compartment model with first-order absorption described the plasma data well. The cellular phosphorylation kinetics was described by a one-compartment model for RMP, with the formation rate driven by plasma concentrations and the first-order degradation rate. RDP and RTP rapidly reached equilibrium with RMP. Concomitant telaprevir use, inosine triphosphatase genetics, creatinine clearance, weight, and sex were significant covariates. The terminal ribavirin half-life in plasma and phosphorylated anabolites in cells was approximately 224 h. We found no evidence of time-dependent kinetics. These data provide a foundation for uncovering concentration-effect associations for ribavirin and determining the optimal dose and duration of this drug for use in combination with newer direct-acting HCV agents. (This study has been registered at ClinicalTrials.gov under registration no. NCT01097395.).
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Dienstag JL, Delemos AS. Viral Hepatitis. MANDELL, DOUGLAS, AND BENNETT'S PRINCIPLES AND PRACTICE OF INFECTIOUS DISEASES 2015:1439-1468.e7. [DOI: 10.1016/b978-1-4557-4801-3.00119-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Chayama K, Mitsui F, Hayes CN. Optimizing triple therapy and IFN/RBV-free regimens for hepatitis C virus infection. Expert Rev Gastroenterol Hepatol 2015; 9:21-30. [PMID: 25220206 DOI: 10.1586/17474124.2015.960394] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Treatment of chronic hepatitis C virus infection has substantially improved following the advent of direct acting antiviral (DAA) agents. Although the first generation protease inhibitors telaprevir and boceprevir improved sustained viral response (SVR) rates, adverse events remain severe and immature termination of the therapy is frequent; however, intensive dose modification has improved completion and SVR rates. Interferon-free DAA combination therapies, such as asunaprevir and daclatasvir dual therapy are under development and promise higher SVR rates with fewer adverse events. Resistance monitoring and modification of DAA therapy based on pre-existing or de novo resistance variants should be considered. Future therapies are expected to have pan-genotypic activity with shorter duration and improved tolerability, even among cirrhotic and liver transplant patients.
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Affiliation(s)
- Kazuaki Chayama
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan
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Allegra S, Cusato J, De Nicolò A, Boglione L, Gatto A, Cariti G, Di Perri G, D'Avolio A. Role of pharmacogenetic in ribavirin outcome prediction and pharmacokinetics in an Italian cohort of HCV-1 and 4 patients. Biomed Pharmacother 2014; 69:47-55. [PMID: 25661337 DOI: 10.1016/j.biopha.2014.10.030] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2014] [Accepted: 10/27/2014] [Indexed: 02/07/2023] Open
Abstract
Ribavirin is phosphorylated by adenosine kinase 1 (AK1) and cytosolic 5'-nucleotidase 2 and it is transported into cells by concentrative nucleoside transporters (CNT) 2/3, coded by SLC28A2/3 genes, and equilibrative nucleoside transporters (ENT) 1/2, coded by SLC29A1/2 genes. We evaluated the association of some polymorphisms of IL28B, SLC28A2/3, SLC29A1, ABCB1, NT5C2, AK1, HNF4α genes and ribavirin treatment outcome and pharmacokinetics after 4weeks of therapy, in a cohort of HCV-1/4 Italian patients. Allelic discrimination was performed by real-time PCR; plasma concentrations were determined at the end of dosing interval (Ctrough) using an HPLC-UV method. Non response was negatively predicted by cryoglobulinemia and IL28B_rs12980275 AA genotype and positively by Metavir score; Metavir score, insulin resistance and SLC28A2_rs1060896 CA/AA and HNF4α_rs1884613 CC genotypes were negative predictive factors of SVR, whereas HCV viral load at baseline and IL28B_rs12980275 AA and rs8099917 TT genotypes positively predicted this outcome; RVR was negatively predicted by insulin resistance and positively by cryoglobulinemia and IL28B_rs12980275 AA genotype; Metavir score and insulin resistance were able to negatively predict EVR, whereas cryoglobulinemia and IL28B_rs12980275 AA genotype positively predicted it; at last, virological relapse was negatively predicted by IL28B_rs8099917 TT and AK1_rs1109374 TT genotypes, insulin resistance was a positive predictor factor. Concerning ribavirin pharmacokinetics, SLC28A2_rs11854488 TT was related to lower Ctrough levels; conversely patients with TC profile of SLC28A3_rs10868138 and SLC29A1_rs760370 GG genotype had higher ribavirin levels. These results might contribute to the clarification of mechanisms causing the individuality in the response to ribavirin containing therapy.
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Affiliation(s)
- Sarah Allegra
- Laboratory of Clinical Pharmacology and Pharmacogenetics(2), Unit of Infectious Diseases, University of Turin, Department of Medical Sciences, Amedeo di Savoia Hospital, Corso Svizzera 164, 10149 Turin, Italy
| | - Jessica Cusato
- Laboratory of Clinical Pharmacology and Pharmacogenetics(2), Unit of Infectious Diseases, University of Turin, Department of Medical Sciences, Amedeo di Savoia Hospital, Corso Svizzera 164, 10149 Turin, Italy.
| | - Amedeo De Nicolò
- Laboratory of Clinical Pharmacology and Pharmacogenetics(2), Unit of Infectious Diseases, University of Turin, Department of Medical Sciences, Amedeo di Savoia Hospital, Corso Svizzera 164, 10149 Turin, Italy
| | - Lucio Boglione
- Laboratory of Clinical Pharmacology and Pharmacogenetics(2), Unit of Infectious Diseases, University of Turin, Department of Medical Sciences, Amedeo di Savoia Hospital, Corso Svizzera 164, 10149 Turin, Italy
| | - Alberto Gatto
- Laboratory of Clinical Pharmacology and Pharmacogenetics(2), Unit of Infectious Diseases, University of Turin, Department of Medical Sciences, Amedeo di Savoia Hospital, Corso Svizzera 164, 10149 Turin, Italy
| | - Giuseppe Cariti
- Laboratory of Clinical Pharmacology and Pharmacogenetics(2), Unit of Infectious Diseases, University of Turin, Department of Medical Sciences, Amedeo di Savoia Hospital, Corso Svizzera 164, 10149 Turin, Italy
| | - Giovanni Di Perri
- Laboratory of Clinical Pharmacology and Pharmacogenetics(2), Unit of Infectious Diseases, University of Turin, Department of Medical Sciences, Amedeo di Savoia Hospital, Corso Svizzera 164, 10149 Turin, Italy
| | - Antonio D'Avolio
- Laboratory of Clinical Pharmacology and Pharmacogenetics(2), Unit of Infectious Diseases, University of Turin, Department of Medical Sciences, Amedeo di Savoia Hospital, Corso Svizzera 164, 10149 Turin, Italy
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Quiles-Pérez R, Muñoz-de-Rueda P, Maldonado AML, Martín-Álvarez A, Quer J, Salmerón J. Effects of ribavirin monotherapy on the viral population in patients with chronic hepatitis C genotype 1: direct sequencing and pyrosequencing of the HCV regions. J Med Virol 2014; 86:1886-97. [PMID: 25091333 DOI: 10.1002/jmv.24035] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/04/2014] [Indexed: 11/11/2022]
Abstract
Ribavirin remains essential to chronic hepatitis C treatment. This paper investigates the influence of ribavirin priming to steady state before combined pegylated-interferon/ribavirin treatment on viral kinetics, ribavirin trough concentrations, genetic variability within HCV-core, -NS5B and -NS5A, and response to antiviral therapy. A prospective cohort study was made of 27 chronic hepatitis C genotype 1 naïve patients who received four weeks of ribavirin followed by pegIFN-α-2a/ribavirin for 48 weeks (Group A). The results obtained were compared with those for a control/historical group (Group B). In addition, direct sequencing and pyrosequencing were applied to determine ribavirin monotherapy-induced sequence changes. The rapid, early, and sustained virological response values obtained were 48%, 89%, and 52%, respectively, in Group A, and 52%, 90%, and 52% in Group B (P > 0.05). In the four-week combined treatment, the Group A patients showed a greater decrease in HCV-RNA (2.3 log10 IU/ml vs. 1.2 log10 IU/ml; P = 0.04), lower alanine aminotransferase levels (23.5 ± 1.33 U/L vs. 60.11 ± 18 U/L; P < 0.001) and higher mean ribavirin trough concentrations (3.28 ± 1.26 mg/L vs. 1.74 ± 0.7 mg/L; P = 0.001). No general increase in rates of nucleotide substitutions in the ribavirin monotherapy-treated patients was observed in NS5B, ISDR, or PKRbd, but there was a decrease in silent mutations in the HCV core (P = 0.04). This result was confirmed by pyrosequencing in the NS5A region. It is concluded that the ribavirin priming combined treatment with pegIFN-α-2a does not improve sustained virological response rates in HCV genotype 1 naïve infected patients. However, the greater reductions in viral load and alanine aminotransferase levels, together with the higher ribavirin trough concentration values obtained, could reflect the greater effectiveness of the treatment. Ribavirin does not have a mutagenic effect on the virus in patients with chronic hepatitis C.
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Affiliation(s)
- R Quiles-Pérez
- Research Support Unit, UNAI, San Cecilio University Hospital, Granada, Spain; CIBEREHD, Spain
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Juda P, Smigová J, Kováčik L, Bártová E, Raška I. Ultrastructure of cytoplasmic and nuclear inosine-5'-monophosphate dehydrogenase 2 "rods and rings" inclusions. J Histochem Cytochem 2014; 62:739-50. [PMID: 24980853 DOI: 10.1369/0022155414543853] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Inosine-5'-monophosphate dehydrogenase catalyzes the critical step in the de novo synthesis of guanosine nucleotides: the oxidation of inosine monophosphate to xanthosine monophosphate. This reaction can be inhibited by specific inhibitors, such as ribavirin or mycophenolic acid, which are widely used in clinical treatment when required to inhibit the proliferation of viruses or cells. However, it was recently found that such an inhibition affects the cells, leading to a redistribution of IMPDH2 and the appearance of IMPDH2 inclusions in the cytoplasm. According to their shape, these inclusions have been termed "Rods and Rings" (R&R). In this work, we focused on the subcellular localization of IMPDH2 protein and the ultrastructure of R&R inclusions. Using microscopy and western blot analysis, we show the presence of nuclear IMPDH2 in human cells. We also show that the nuclear pool has an ability to form Rod structures after inhibition by ribavirin. Concerning the ultrastructure, we observed that R&R inclusions in cellulo correspond to the accumulation of fibrous material that is not surrounded by a biological membrane. The individual fibers are composed of regularly repeating subunits with a length of approximately 11 nm. Together, our findings describe the localization of IMPDH2 inside the nucleus of human cells as well as the ultrastructure of R&R inclusions.
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Affiliation(s)
- Pavel Juda
- Charles University in Prague, First Faculty of Medicine, Institute of Cellular Biology and Pathology, Czech Republic (PJ, JS, LK, IR)Institute of Biophysics, Academy of Sciences of the Czech Republic, v.v.i., Brno, Czech Republic (EB)
| | - Jana Smigová
- Charles University in Prague, First Faculty of Medicine, Institute of Cellular Biology and Pathology, Czech Republic (PJ, JS, LK, IR)Institute of Biophysics, Academy of Sciences of the Czech Republic, v.v.i., Brno, Czech Republic (EB)
| | - Lubomír Kováčik
- Charles University in Prague, First Faculty of Medicine, Institute of Cellular Biology and Pathology, Czech Republic (PJ, JS, LK, IR)Institute of Biophysics, Academy of Sciences of the Czech Republic, v.v.i., Brno, Czech Republic (EB)
| | - Eva Bártová
- Charles University in Prague, First Faculty of Medicine, Institute of Cellular Biology and Pathology, Czech Republic (PJ, JS, LK, IR)Institute of Biophysics, Academy of Sciences of the Czech Republic, v.v.i., Brno, Czech Republic (EB)
| | - Ivan Raška
- Charles University in Prague, First Faculty of Medicine, Institute of Cellular Biology and Pathology, Czech Republic (PJ, JS, LK, IR)Institute of Biophysics, Academy of Sciences of the Czech Republic, v.v.i., Brno, Czech Republic (EB)
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Markova AA, Mihm U, Schlaphoff V, Lunemann S, Filmann N, Bremer B, Berg T, Sarrazin C, Zeuzem S, Manns MP, Cornberg M, Herrmann E, Wedemeyer H. PEG-IFN alpha but not ribavirin alters NK cell phenotype and function in patients with chronic hepatitis C. PLoS One 2014; 9:e94512. [PMID: 24751903 PMCID: PMC3994015 DOI: 10.1371/journal.pone.0094512] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2013] [Accepted: 03/17/2014] [Indexed: 12/11/2022] Open
Abstract
Background Ribavirin (RBV) remains part of several interferon-free treatment strategies even though its mechanisms of action are still not fully understood. One hypothesis is that RBV increases responsiveness to type I interferons. Pegylated Interferon alpha (PEG-IFNa) has recently been shown to alter natural killer (NK) cell function possibly contributing to control of hepatitis C virus (HCV) infection. However, the effects of ribavirin alone or in combination with IFNa on NK cells are unknown. Methods Extensive ex vivo phenotyping and functional analysis of NK cells from hepatitis C patients was performed during antiviral therapy. Patients were treated for 6 weeks with RBV monotherapy (n = 11), placebo (n = 13) or PEG-IFNa-2a alone (n = 6) followed by PEG-IFNa/RBV combination therapy. The effects of RBV and PEG-IFNa-2a on NK cells were also studied in vitro after co-culture with K562 or Huh7.5 cells. Results Ribavirin monotherapy had no obvious effects on NK cell phenotype or function, neither ex vivo in patients nor in vitro. In contrast, PEG-IFNa-2a therapy was associated with an increase of CD56bright cells and distinct changes in expression profiles leading to an activated NK cell phenotype, increased functionality and decline of terminally differentiated NK cells. Ribavirin combination therapy reduced some of the IFN effects. An activated NK cell phenotype during therapy was inversely correlated with HCV viral load. Conclusions PEG-IFNa activates NK cells possibly contributing to virological responses independently of RBV. The role of NK cells during future IFN-free combination therapies including RBV remains to be determined.
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Affiliation(s)
- Antoaneta A. Markova
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Ulrike Mihm
- Department of Medicine 1, JW Goethe-University Hospital, Frankfurt am Main, Germany
| | - Verena Schlaphoff
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Sebastian Lunemann
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Natalie Filmann
- Institute of Biostatistics and Mathematical Modelling, Faculty of Medicine, JW Goethe-University, Frankfurt am Main, Germany
| | - Birgit Bremer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Thomas Berg
- Department of Internal Medicine, Division of Gastroenterology and Rheumatology, University of Leipzig, Leipzig, Germany
| | - Christoph Sarrazin
- Department of Medicine 1, JW Goethe-University Hospital, Frankfurt am Main, Germany
| | - Stefan Zeuzem
- Department of Medicine 1, JW Goethe-University Hospital, Frankfurt am Main, Germany
| | - Michael P. Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Markus Cornberg
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Eva Herrmann
- Institute of Biostatistics and Mathematical Modelling, Faculty of Medicine, JW Goethe-University, Frankfurt am Main, Germany
| | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
- * E-mail:
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Wohl BM, Smith AAA, Kryger MBL, Zelikin AN. Narrow therapeutic window of ribavirin as an inhibitor of nitric oxide synthesis is broadened by macromolecular prodrugs. Biomacromolecules 2013; 14:3916-26. [PMID: 24156371 DOI: 10.1021/bm401048s] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Ribavirin (RBV), a broad-spectrum antiviral agent, is a standard medication against hepatitis C virus (HCV). However, despite the decades of clinical success, the mechanism of action of this drug against HCV remains a subject of debate. Furthermore, the appeal of this therapeutic agent is considerably lessened by unfavorable pharmacokinetics. This interdisciplinary study contributes to the understanding of intracellular effects exerted by RBV and presents a successful design of macromolecular prodrugs of RBV to achieve a safer treatment. Specifically, we demonstrate that RBV exhibits a pronounced anti-inflammatory activity in cultured macrophages as is evidenced by a 2-fold decrease in the levels of produced nitric oxide achieved using a clinically relevant concentration of this drug. However, this effect was characterized by a rather narrow therapeutic window with experimental values of EC50 and IC50 being 7 and 19 μM, respectively. Macromolecular prodrugs were obtained using an acrylate derivative of RBV, RAFT polymerization technique, and N-vinyl pyrrolidone as a partner monomer. The synthesized polymers were characterized with uniform molecular weights, relatively narrow polydispersities, and gradually increasing content of RBV. The resulting polymer therapeutics were effective in delivering their payload to the cultured macrophages and afforded a significantly wider therapeutic window, as much as >1000 μM (18-fold in relative values). Taken together, this work contributes significantly to the development of safer methods for delivery of RBV, as well as understanding the mechanism of action and origins of the side effects of this broad-spectrum antiviral agent.
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Affiliation(s)
- Benjamin M Wohl
- Department of Chemistry and ‡iNano Interdisciplinary Nanoscience Centre, Aarhus University , Aarhus 8000, Denmark
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Hepatitis C virus infection: looking for interferon free regimens. ScientificWorldJournal 2013; 2013:825375. [PMID: 23710151 PMCID: PMC3654259 DOI: 10.1155/2013/825375] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2013] [Accepted: 03/04/2013] [Indexed: 02/06/2023] Open
Abstract
Recent developments of new drugs' combinations are changing the treatment paradigm in hepatitis C virus infection. Due to the side effect profile of pegylated interferons, interferon-sparing regimens have become the main target in chronic hepatitis C treatment research. Recent proofs of concept studies have suggested that cure of chronic hepatitis C can be achieved without interferon. The purpose of this paper is to provide an overview of the clinical results recently reported for the treatment of hepatitis C virus infection with interferon-free regimens, focusing on the most promising new compounds and combinations.
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Deep sequencing reveals mutagenic effects of ribavirin during monotherapy of hepatitis C virus genotype 1-infected patients. J Virol 2013; 87:6172-81. [PMID: 23536652 DOI: 10.1128/jvi.02778-12] [Citation(s) in RCA: 82] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
The preeminent mode of action of the broad-spectrum antiviral nucleoside ribavirin in the therapy of chronic hepatitis C is currently unresolved. Particularly under contest are possible mutagenic effects of ribavirin that may lead to viral extinction by lethal mutagenesis of the hepatitis C virus (HCV) genome. We applied ultradeep sequencing to determine ribavirin-induced sequence changes in the HCV coding region (nucleotides [nt] 330 to 9351) of patients treated with 6-week ribavirin monotherapy (n = 6) in comparison to placebo (n = 6). Baseline HCV RNA levels maximally declined on average by -0.8 or -0.1 log10 IU/ml in ribavirin- versus placebo-treated patients. No general increase in rates of nucleotide substitutions in ribavirin-treated patients was observed. However, more HCV genome positions with high G-to-A and C-to-U transition rates were detected between baseline and treatment week 6 in ribavirin-treated patients in comparison to placebo-treated patients (rate of 0.0041 transitions per base pair versus rate of 0.0022 transitions per base pair; P = 0.049). Similarly, the sensitive detection of low-frequency minority variants by statistical filtering indicated significantly more positions with G-to-A and C-to-U transitions in ribavirin-treated patients than in placebo-treated patients (rate of 0.0331 transitions versus rate of 0.0186 transitions per G/C-containing position at baseline; P = 0.018). In contrast, non-ribavirin-associated A-to-G and U-to-C transitions were not enriched in the ribavirin group (P = 0.152). We conclude that ribavirin exerts a mutagenic effect on the virus in patients with chronic hepatitis C by facilitating G-to-A and C-to-U nucleotide transitions.
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Lee J, Choi YS, Shin EC. Ribavirin Does Not Impair the Suppressive Activity of Foxp3(+)CD4(+)CD25(+) Regulatory T Cells. Immune Netw 2013; 13:25-9. [PMID: 23559897 PMCID: PMC3607707 DOI: 10.4110/in.2013.13.1.25] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2012] [Revised: 01/03/2013] [Accepted: 01/09/2013] [Indexed: 12/18/2022] Open
Abstract
Ribavirin is an antiviral drug used in combination with pegylated interferon-α (IFN-α) for the treatment of hepatitis C virus (HCV) infection. Recently, ribavirin was reported to inhibit the suppressive activity of regulatory T (Treg) cells. In the present study, we re-evaluated the effect of ribavirin on Foxp3+CD4+CD25+ Treg cells from normal donors. First, we examined the expression of CTLA-4 and CD39, which are known to play a role in the suppressive function of Treg cells. We found that ribavirin treatment did not modulate the expression of CTLA-4 and CD39 in Treg cells. We also studied the effect of ribavirin on Treg cells in the presence of IFN-α; however, the expression of CTLA-4 and CD39 in Treg cells was not changed by ribavirin in the presence of IFN-α. Next, we directly evaluated the effect of ribavirin on the suppressive activity of Treg cells in the standard Treg suppression assay, by co-culturing CFSE-labeled non-Treg CD4+ T cells with purified Treg cells. We found that ribavirin did not attenuate the suppressive activity of Treg cells. Taken together, while ribavirin reversed Treg cell-mediated suppression of effector T cells in the previous study, we herein demonstrate that ribavirin does not impair the suppressive activity of Treg cells.
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Affiliation(s)
- Jeewon Lee
- Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, KAIST, Daejeon 305-701, Korea
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Probst C, Radzimski C, Blöcker IM, Teegen B, Bogdanos DP, Stöcker W, Komorowski L. Development of a recombinant cell-based indirect immunofluorescence assay (RC-IFA) for the determination of autoantibodies against "rings and rods"-associated inosine-5'-monophosphate dehydrogenase 2 in viral hepatitis C. Clin Chim Acta 2013; 418:91-6. [PMID: 23333419 DOI: 10.1016/j.cca.2013.01.003] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2012] [Revised: 01/08/2013] [Accepted: 01/08/2013] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIMS Autoantibodies against so-called "rings and rods" structures, as determined by indirect immunofluorescence assay (IFA) using the human cell line HEp-2, have been described in chronic hepatitis C virus (HCV) infected patients treated with interferon/ribavirin. Recently, cytidine triphosphate synthase (CTPS) and inosine-5'-monophosphate dehydrogenase 2 (IMPDH2), the enzyme inhibited by ribavirin, were proposed as the target antigens. We wanted to confirm the identification and setup a robust system for autoantibody testing in routine laboratories. METHODS CTPS and IMPDH2 were individually expressed in HEK293 cells and the recombinant cells were used in IFA (RC-IFA) to analyze sera from 33 anti-"rings and rods" antibody positive individuals with unknown diagnosis, 50 patients with chronic HCV infection, 100 with autoimmune hepatitis, 50 with primary biliary cirrhosis and 50 healthy blood donors. RESULTS We found that all sera with anti-"rings and rods" reacted with recombinant IMPDH2 but none with CTPS. In western blot or ELISA, anti-IMPDH2 positive sera reacted only weakly, if at all, with Escherichia coli derived recombinant IMPDH2 indicating that the autoantibody reaction probably depends on the 3-dimensional conformation of the antigen. A rabbit hyperimmune serum raised against bacterially expressed IMPDH2 produced the ring/rods pattern in IFA using HEp-2. CONCLUSIONS We conclude, that IMPDH2 is indeed the main target of anti-"rings and rods" while CTPS is an unlikely target. Moreover, the novel RC-IFA test system allows a standardized semi-quantitative determination of anti-IMPDH2 basing on a defined recombinant antigen.
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Affiliation(s)
- Christian Probst
- Institute of Experimental Immunology, EUROIMMUN AG, Lübeck, Germany
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Castilho MCB, Martins AN, Horbach IS, Perez RDM, Figueiredo FAF, Pinto PDTA, Nabuco LC, Lima DBD, Tanuri A, Porto LC, Ferreira Júnior ODC. Association of hepatitis C virus NS5B variants with resistance to new antiviral drugs among untreated patients. Mem Inst Oswaldo Cruz 2012; 106:968-75. [PMID: 22241118 DOI: 10.1590/s0074-02762011000800011] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2011] [Accepted: 09/08/2011] [Indexed: 01/06/2023] Open
Abstract
Mutations located in the 109-amino acid fragment of NS5B are typically associated with resistance to interferon (IFN) and ribavirin (RIB) and to new antiviral drugs. The prevalence of these mutations was examined in 69 drug-naïve individuals with hepatitis C virus (HCV) infections in Rio de Janeiro, Brazil. Mutations related to non-response to IFN/RIB were observed in all subtypes studied (1a, 1b, 2b, 3a and 4). The most common mutation was Q309R, present in all subtypes, except subtype 2b with frequency above 20%. D244N was detected only in subtype 3a and A333E was detected only in subtype 2b. We did not detect the S282T, S326G or T329I mutations in any of the samples analysed. Of note, the C316N mutation, previously related to a new non-nucleoside compound (HCV796 and AG-021541), was observed in only eight of 33 (24%) samples from subtype 1b. Site 316 was under positive selection in this HCV variant. Our data highlight the presence of previously described resistance mutations in HCV genotypes from drug-naïve patients.
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Affiliation(s)
- Magda Cristina Bernardino Castilho
- Laboratório de Histocompatibilidade e Criopreservação, Policlínica Piquet Carneiro, Departamento de Histologia e Embriologia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brasil.
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Keppeke GD, Nunes E, Ferraz MLG, Silva EAB, Granato C, Chan EKL, Andrade LEC. Longitudinal study of a human drug-induced model of autoantibody to cytoplasmic rods/rings following HCV therapy with ribavirin and interferon-α. PLoS One 2012; 7:e45392. [PMID: 23028980 PMCID: PMC3454395 DOI: 10.1371/journal.pone.0045392] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2012] [Accepted: 08/22/2012] [Indexed: 12/29/2022] Open
Abstract
Background A novel pattern in the indirect immunofluorescence antinuclear antibody assay on HEp-2 cells (IIF-HEp-2) characterized by cytoplasmic rods and rings (RR) was reported in HCV patients, but stringent disease specificity studies and longitudinal analysis are lacking. We investigated the clinical significance of anti-RR in an HCV cohort with up to a 12-month treatment follow up. Methodology/Results 597 patients (342 HCV, 55 HCV/HIV, 200 non-HCV) were screened and titered for anti-RR. Serial samples were available from 78 of 176 treated and 27 of 166 untreated patients. Anti-RR was detected in 14.1% of 342 HCV patients, 9.1% of 55 HCV/HIV, 3.4% of 29 Hepatitis B, and none of 171 non-HCV (p<0.0001; HCV versus non-HCV). Anti-RR was present in 38% of 108 patients receiving interferon-α/ribavirin, but none in 26 receiving either interferon-α or ribavirin, or 166 untreated patients (p<0.0001). Other IIF-HEp-2 patterns were more frequently associated with interferon-α treatment alone (52.2%) as compared to interferon-α/ribavirin (25%), ribavirin alone (33.3%), and no therapy (26.5%). Anti-RR frequency was not associated with sex, age, ethnicity, HCV genotype or viral load. Anti-RR occurred only after initiation of treatment, beginning as early as 1 month (6%), but by the sixth month >47% tested positive for anti-RR. The anti-RR titer generally increased with sustained treatment and remained high in 53% of patients. After treatment, anti-RR titer was negative in 41%. Non-responders to HCV therapy were 77% in anti-RR-positive versus 64% in anti-RR-negative patients. Response to treatment was not associated with anti-RR titer or the dynamics of anti-RR reactivity during and after treatment. Conclusions The exquisite association of anti-RR reactivity with combined interferon-α/ribavirin therapy in HCV patients represents a unique model for drug-induced autoantibody generation in humans as demonstrated by the fact that a significant fraction of patients who have anti-RR during therapy becomes anti-RR-negative after completion of therapy.
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Affiliation(s)
| | - Eunice Nunes
- Gastroenterology Division, Universidade Federal de São Paulo, São Paulo, Brazil
| | | | | | - Celso Granato
- Infectious Diseases Division, Universidade Federal de São Paulo, São Paulo, Brazil
- Immunology Division, Fleury Medicine and Health Laboratories, São Paulo, Brazil
| | - Edward K. L. Chan
- Department of Oral Biology, University of Florida, Gainesville, Florida, United States of America
| | - Luís Eduardo C. Andrade
- Rheumatology Division, Universidade Federal de São Paulo, São Paulo, Brazil
- Immunology Division, Fleury Medicine and Health Laboratories, São Paulo, Brazil
- * E-mail:
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Örmeci N, Erdem H. Basic answers to complicated questions for the course of chronic hepatitis C treatment. Expert Rev Gastroenterol Hepatol 2012; 6:371-82. [PMID: 22646258 DOI: 10.1586/egh.12.16] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Hepatitis C virus infection is a long-lasting disease, which causes chronic hepatitis, liver cirrhosis and hepatocellular carcinoma, thus leading to liver-related death. Currently, the optimal treatment for chronic hepatitis C infection is the combination of pegylated interferon and ribavirin. The aim of this review is to assess the long-term clinical outcomes of interferons alone or in combination with ribavirin in the management of chronic hepatitis C.
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Affiliation(s)
- Necati Örmeci
- Department of Gastroenterology, Ankara University School of Medicine, Ankara, Turkey
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Tsubota A, Shimada N, Yoshizawa K, Furihata T, Agata R, Yumoto Y, Abe H, Ika M, Namiki Y, Chiba K, Fujise K, Tada N, Aizawa Y. Contribution of ribavirin transporter gene polymorphism to treatment response in peginterferon plus ribavirin therapy for HCV genotype 1b patients. Liver Int 2012; 32:826-36. [PMID: 22212648 DOI: 10.1111/j.1478-3231.2011.02727.x] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2011] [Accepted: 11/20/2011] [Indexed: 12/17/2022]
Abstract
BACKGROUND Standard-dose ribavirin is crucial for the standard-of-care treatment of chronic hepatitis C virus (HCV) infection. Equilibrative nucleoside transporter 1 (ENT1), encoded by SLC29A1 gene, is the main transporter that imports ribavirin into human hepatocytes. AIMS To determine whether single nucleotide polymorphisms (SNPs) at the SLC29A1 gene could influence the probability of treatment response compared with other baseline and host genetic factors. METHODS A total of 526 East Asian patients monoinfected with HCV genotype 1b who had received pegylated interferon alpha plus ribavirin therapy were enrolled in this study. They were assigned randomly to the derivation and confirmatory groups. SNPs related to the IL28B, ITPA and SLC29A1 genes were genotyped using real-time detection polymerase chain reaction. Factors associated with sustained virological response (SVR) were analysed using multiple logistic regression analysis. RESULTS Multivariate analysis for the derivation group identified six baseline variables significantly and independently associated with SVR: age [P = 0.023, odds ratio (OR) = 0.97], gender (P = 0.0047, OR = 2.25), platelet count (P = 0.00017, OR = 1.11), viral load (P = 0.00026, OR = 0.54), IL28B SNP rs12979860 (P = 1.09 × 10(-7) , OR = 8.68) and SLC29A1 SNP rs6932345 (P = 0.030, OR = 1.85). Using the model constructed by these independent variables, positive and negative predictive values and predictive accuracy were 73.3, 70.1 and 71.9% respectively. For the confirmatory group, they were 71.4, 84.6 and 75.3% respectively. The SLC29A1 and IL28B SNPs were also significantly associated with rapid virological response. CONCLUSIONS The SNP at the major ribavirin transporter ENT1 gene SLC29A1 was one of significantly independent factors influencing treatment response, although the impact on the prediction was small.
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Affiliation(s)
- Akihito Tsubota
- Institute of Clinical Medicine and Research (ICMR), Jikei University School of Medicine, Kashiwa, Chiba, Japan
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Jia Y, Polunovsky V, Bitterman PB, Wagner CR. Cap-dependent translation initiation factor eIF4E: an emerging anticancer drug target. Med Res Rev 2012; 32:786-814. [PMID: 22495651 PMCID: PMC7168506 DOI: 10.1002/med.21260] [Citation(s) in RCA: 88] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Cancer cells tend to be more highly dependent on cap‐dependent translation than normal tissues. Thus, proteins involved in the initiation of cap‐dependent translation have emerged as potential anti‐cancer drug targets. Cap‐dependent translation is initiated by the binding of the factor eIF4E to the cap domain of mRNA. Detailed x‐ray crystal and NMR structures are available for eIF4E in association with cap‐analogs, as well as domains of other initiation factors. This review will summarize efforts to design potential antagonist of eIF4E that could be used as new pharmacological tools and anti‐cancer agents and. Insights drawn from these studies should aid in the design of future inhibitors of eIF4E dependent translation initiation. © 2012 Wiley Periodicals, Inc. Med Res Rev., 32, No. 4, 786‐814, 2012
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Affiliation(s)
- Yan Jia
- Department of Chemistry, University of Minnesota, Minneapolis, MN 55455, USA
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Lee LY, Tong CYW, Wong T, Wilkinson M. New therapies for chronic hepatitis C infection: a systematic review of evidence from clinical trials. Int J Clin Pract 2012; 66:342-55. [PMID: 22420497 DOI: 10.1111/j.1742-1241.2012.02895.x] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
INTRODUCTION Hepatitis C virus (HCV) affects approximately 3% of the world population. The current standard of care for treatment of HCV is a combination of pegylated interferon and ribavirin. Approximately 10% of patients will stop treatment and 30% of patients require dose reduction because of side effects. For genotype 1 HCV-infected patients, only 40% of patients will achieve undetectable viral load 26 weeks posttreatment. AIMS The objectives of this review were to identify new treatments that are in clinical trials. These include boceprevir and telaprevir which are in routine clinical use and form part of the American Association for the Study of Liver Diseases (AASLD) 2011 guidelines as well as drugs based on observational studies, improving/modifying ribavirin or interferon-based therapies, modifying the host response and finally the use of direct-acting antiviral agents (DAA). MATERIALS AND METHODS MEDLINE and EMBASE databases were searched from 2008 to 2011 for treatments for hepatitis C. Furthermore, abstracts and poster presentations for the annual European Association Study of the Liver, AASLD, Digestive Disease Week and Asian Pacific Association for the study of the Liver were searched for relevant material. RESULTS All four classes of DAA; NS3/NS4a serine protease inhibitors, cyclophilin inhibitors, NS5b polymerase inhibitors and NS5a inhibitors, show good success rates. Trials have been performed without ribavirin or interferon and demonstrate good antiviral activity with a decreased side effect profile. Combinations of DAA are a promising area of research with a high success rate. CONCLUSIONS Clinical trials show that future HCV therapy could be personalised, achieve higher success rates with decreased adverse incidents.
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Affiliation(s)
- L Y Lee
- Guy's and St Thomas's NHS Foundation Trust, London, UK.
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Molina Pérez E, Fernández Castroagudín J, Domínguez Muñoz E. [Current indications for triple therapy in hepatitis C virus infection]. GASTROENTEROLOGIA Y HEPATOLOGIA 2012; 35:266-77. [PMID: 22410706 DOI: 10.1016/j.gastrohep.2012.01.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/10/2012] [Accepted: 01/19/2012] [Indexed: 10/28/2022]
Abstract
Chronic hepatitis C virus (HCV) infection is the main cause of liver cirrhosis and liver carcinoma in western countries. There is evidence that HCV clearance induced by antiviral therapy is beneficial, increasing survival and reducing the complications of cirrhosis. Triple therapy with boceprevir or telaprevir associated with pegylated interferon and ribavirin has increased rates of sustained viral response both in treatment-naïve patients and in those failing previous regimens. Before treating patients with these new molecules, physicians should be familiar with their indications and the regimens to be used. Furthermore, both adverse events and the development of resistances must be monitored. The main aims are careful selection of patients and of the regimen to be used, and achieving adequate adherence to obtain optimal results.
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Affiliation(s)
- Esther Molina Pérez
- Unidad de Hepatología, Servicio de Aparato Digestivo, Hospital Clínico Universitario de Santiago, Santiago de Compostela, España
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Halfon P, Sarrazin C. Future treatment of chronic hepatitis C with direct acting antivirals: is resistance important? Liver Int 2012; 32 Suppl 1:79-87. [PMID: 22212577 DOI: 10.1111/j.1478-3231.2011.02716.x] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Recent advances in molecular biology have led to the development of novel small molecules that target specific viral proteins of the hepatitis C virus (HCV) life cycle. These drugs, collectively termed directly acting antivirals (DAA), include a range of non-structural (NS) 3/NS4A protease, NS5B polymerase and NS5A inhibitors at various stages of clinical development. Some others drugs called 'non DAA'or indirect inhibitors are not focused on one site of the life cycle target and are still in early pre-clinical and clinical phase I, II and III trials. The rapid replication rate of HCV, along with the low fidelity of its polymerase, results in a generation of mutations throughout the viral genome and sequence variation in the HCV population known as a quasispecies. The efficacy of DAA is limited by the presence of these mutations, resulting in amino acid substitutions within the targeted proteins which affect viral sensitivity to these compounds. Thus, attributable to the high genetic variability of HCV, variants with reduced susceptibility to DAA can occur naturally even before treatment begins, but usually at low levels. Thus it is not surprising that these changes are selected in patients that either breakthrough or do not respond to potent DAA treatment. Six major position mutations in the NS3 HCV Protease (36, 54, 155, 156, 168 and 170), fifteen in the NS5B polymerase (96, 282, 316, 365, 414, 419, 423, 448, 482, 494, 495, 496, 499, 554, 559) and five in the NS5 A region (28, 30, 31, 58 and 93) have now been reported in vitro or in vivo associated with different levels of resistance. The amino acid composition at several of the drug resistance sites can vary between the HCV genotypes/subtypes, resulting in different consensus amino acids leading to a reduction in replicative fitness as well as reduced DAA and non- DAA sensitivity. Information on patterns of resistance to and cross resistance between antiviral agents is increasingly available and may be important for decisions on how to combine drugs to achieve an optimum antiviral effect. This review debates the clinical relevance of resistance to direct and indirect inhibitors taking into account the future potential therapeutic strategies to help patients who do develop resistance to HCV inhibitors. Finally, this chapter treats two points of view: 'for' and 'against' the question of the importance of resistance.
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Affiliation(s)
- Philippe Halfon
- Virological Departement Laboratoire Alphabio, Hôpital Ambroise Paré, Marseille, France
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