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1
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Joo SK, Kim W. Sex/Gender Differences in Liver Diseases. SEX/GENDER-SPECIFIC MEDICINE IN CLINICAL AREAS 2024:209-217. [DOI: 10.1007/978-981-97-0130-8_7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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2
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Sfogliarini C, Pepe G, Cesta CM, Allegretti M, Locati M, Vegeto E. The immune activity of selective estrogen receptor modulators is gene and macrophage subtype-specific yet converges on Il1b downregulation. Biomed Pharmacother 2023; 165:115008. [PMID: 37442065 DOI: 10.1016/j.biopha.2023.115008] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Revised: 05/29/2023] [Accepted: 06/11/2023] [Indexed: 07/15/2023] Open
Abstract
Raloxifene belongs to the family of Selective Estrogen Receptor Modulators (SERMs), which are drugs widely prescribed for Estrogen Receptor alpha (ERα)-related pathologies. Recently, SERMs are being tested in repurposing strategies for ERα-independent clinical indications, including a wide range of microbial infections. Macrophages are central in the fight against pathogen invasion. Despite estrogens have been shown to regulate macrophage phenotype, SERMs activity in these cells is still poorly defined. We investigated the activity of Raloxifene in comparison with another widely used SERM, Tamoxifen, on immune gene expression in macrophages obtained from mouse and human tissues, including mouse peritoneal macrophages, bone marrow-derived macrophages, microglia or human blood-derived macrophages, assaying for the involvement of the ERα, PI3K and NRF2 pathways also under inflammatory conditions. Our data demonstrate that Raloxifene acts by a dual mechanism, which entails ERα antagonism and off-target mediators. Moreover, micromolar concentrations of Raloxifene increase the expression of immune metabolic genes, such as Vegfa and Hmox1, through PI3K and NRF2 activation selectively in peritoneal macrophages. Conversely, Il1b mRNA down-regulation by SERMs is consistently observed in all macrophage subtypes and unrelated to the PI3K/NRF2 system. Importantly, the production of the inflammatory cytokine TNFα induced by the bacterial endotoxin, LPS, is potentiated by SERMs and paralleled by the cell subtype-specific increase in IL1β secretion. This work extends our knowledge on the biological and molecular mechanisms of SERMs immune activity and indicate macrophages as a pharmacological target for the exploitation of the antimicrobial potential of these drugs.
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Affiliation(s)
- Chiara Sfogliarini
- Department of Pharmaceutical Sciences, University of Milan, 20133 Milan, Italy.
| | - Giovanna Pepe
- Department of Pharmaceutical Sciences, University of Milan, 20133 Milan, Italy.
| | | | | | - Massimo Locati
- IRCCS Humanitas Research Hospital, via Manzoni 56, Rozzano, 20089 Milan, Italy; Department of Medical Biotechnology and Translational Medicine, University of Milan, 20133 Milan, Italy.
| | - Elisabetta Vegeto
- Department of Pharmaceutical Sciences, University of Milan, 20133 Milan, Italy.
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3
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Maddiboyina B, Roy H, Nakkala RK, Gandhi S, Kavisri M, Moovendhan M. Formulation, optimization and characterization of raloxifene hydrochloride loaded PLGA nanoparticles by using Taguchi design for breast cancer application. Chem Biol Drug Des 2023; 102:457-470. [PMID: 36856306 DOI: 10.1111/cbdd.14222] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2022] [Revised: 02/13/2023] [Accepted: 02/24/2023] [Indexed: 03/02/2023]
Abstract
Multidrug resistance in breast cancer and the associated side-effects of anticancer therapies are significant hurdles in chemotherapy-based treatment. Biodegradable polymeric nano-based targeted drug delivery technologies showed tremendous advantages in targeted local delivery with limited off-targeted side effects. Therefore, there is a persistent need to develop targeted nanomedicine systems for treatment of breast cancer. The current research attempted to develop poly (lactic-co-glycolic acid) nanoparticles loaded with raloxifene by modified emulsification solvent diffusion evaporation method to improve oral bioavailability by using Taguchi design. It was observed that the optimized formulation (1:4 drug to polymer ratio) poly (lactic-co-glycolic acid) showed a mean particle size and Polydispersity index of 218 ± 23.7 nm and 0.231 ± 0.04, respectively. The entrapment efficiency was found to be 82.30% ± 1.02%. In vitro drug delivery was found to be 92.5% ± 1.48% in 40 h. The nanoparticles were to remain stable at 2°C-8°C even after 30 days. Differential scanning calorimetry and Fourier transform infrared spectroscopy characterization techniques showed that there was no interaction between the drug and excipient. Stability studies indicate that polymeric nanoparticles were stable at 2°C-8°C after 6 months. Raloxifene nanoparticles may be the most potent targeting moieties to treat highly invasive and metastatic MCF-7 breast cancer cells.
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Affiliation(s)
| | | | | | - Sivaraman Gandhi
- Department of Chemistry, Gandhigram Rural Institute Deemed University, Dindigul, India
| | - M Kavisri
- Department of Civil Engineering, Saveetha School of Engineering, Chennai, India
| | - Meivelu Moovendhan
- Centre for Ocean Research, Col.Dr.Jeppiaar Research Park, Sathyabama Institute of Science and Technology, Chennai, India
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4
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Tsourdi E, Drake MT. Pros and Cons of Skeletal Medications in the COVID-19 Era. CURRENT TREATMENT OPTIONS IN RHEUMATOLOGY 2022; 8:56-69. [PMID: 35875832 PMCID: PMC9287705 DOI: 10.1007/s40674-022-00192-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/14/2022] [Indexed: 11/29/2022]
Abstract
Purpose of Review This review provides an overview regarding osteoporosis therapies during the COVID-19 pandemic. Recent Findings The COVID-19 pandemic has disrupted treatments for osteoporosis and resulted in decreased adherence particularly for parenteral regimens. Osteoporosis medications are safe and effective during the pandemic and should be continued whenever possible. Bisphosphonates have long-lasting effects on bone turnover such that delays in their administration are unlikely to be harmful to skeletal health. In contrast, interruption of denosumab treatment is strongly discouraged because of rapid loss of bone mass and an associated increased risk for rebound vertebral fractures. When osteoanabolic treatments cannot be continued during the pandemic, change to an oral bisphosphonate is advised. Preclinical data suggest possible beneficial effects of some therapies against COVID-19, but require validation in clinical studies. Vitamin D deficiency is associated with a more severe COVID-19 clinical course but data supporting improvements in outcomes with vitamin D supplementation are lacking. Summary The impact of the COVID-19 pandemic on long-term bone health remains unknown but focused interventions to ensure osteoporosis treatment initiation/maintenance should be implemented. Future studies are needed to determine whether osteoporosis medications have an impact on SARS-CoV-2 pathophysiology and COVID-19 clinical outcomes.
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Affiliation(s)
- Elena Tsourdi
- Department of Medicine III, Universitätsklinikum Dresden, Dresden, Germany
- Center for Healthy Aging, Universitätsklinikum Dresden, Dresden, Germany
| | - Matthew T. Drake
- Division of Endocrinology, Diabetes, Metabolism and Nutrition, Mayo Clinic, Rochester, MN USA
- Division of Endocrinology and Robert and Arlene Kogod Center On Aging, Mayo Clinic College of Medicine, Rochester, MN 55905 USA
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5
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Wang P, Gao XS, Zhang YN, Duan XF. Progress in research of non-cirrhotic chronic viral hepatitis with osteoporosis. Shijie Huaren Xiaohua Zazhi 2022; 30:491-497. [DOI: 10.11569/wcjd.v30.i11.491] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Osteoporosis is one of the complications of chronic viral hepatitis related cirrhosis, and the pathogenesis and treatment methods for osteoporosis have been extensively studied. However, whether chronic viral hepatitis is the risk factor for osteoporosis is still controversial. Some studies have demonstrated the relationship between them, but there is still no systematic judgment on its pathogenesis and treatment. In this review, we systematically summarize the risk, possible pathogenesis, and treatment scheme of osteoporosis secondary to non-cirrhosis chronic viral hepatitis, with an aim to clarify the relationship between chronic viral hepatitis and osteoporosis, remind clinicians to be alert to the possibility of osteoporosis complicated by chronic viral hepatitis, and provide support for clinical diagnosis and treatment.
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Affiliation(s)
- Ping Wang
- Department of General Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Xue-Song Gao
- Department of General Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Yao-Nan Zhang
- Orthopedic Department of Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Xue-Fei Duan
- Department of General Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
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6
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Sharma A, Streets J, Bhatt P, Patel P, Sutariya V, Varghese Gupta S. Formulation and Characterization of Raloxifene Nanostructured Lipid Carriers for Permeability and Uptake Enhancement Applications. Assay Drug Dev Technol 2022; 20:164-174. [DOI: 10.1089/adt.2022.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Affiliation(s)
- Anju Sharma
- Department of Pharmaceutical Sciences, Taneja College of Pharmacy, University of South Florida, Tampa, Florida, USA
| | - Jarriaun Streets
- Department of Pharmaceutical Sciences, Taneja College of Pharmacy, University of South Florida, Tampa, Florida, USA
| | - Priyanka Bhatt
- Department of Pharmaceutical Sciences, Wegmans School of Pharmacy, St. John Fisher College, Rochester, New York, USA
| | | | - Vijaykumar Sutariya
- Department of Pharmaceutical Sciences, Taneja College of Pharmacy, University of South Florida, Tampa, Florida, USA
| | - Sheeba Varghese Gupta
- Department of Pharmaceutical Sciences, Taneja College of Pharmacy, University of South Florida, Tampa, Florida, USA
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7
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Iaconis D, Bordi L, Matusali G, Talarico C, Manelfi C, Cesta MC, Zippoli M, Caccuri F, Bugatti A, Zani A, Filippini F, Scorzolini L, Gobbi M, Beeg M, Piotti A, Montopoli M, Cocetta V, Bressan S, Bucci EM, Caruso A, Nicastri E, Allegretti M, Beccari AR. Characterization of raloxifene as a potential pharmacological agent against SARS-CoV-2 and its variants. Cell Death Dis 2022; 13:498. [PMID: 35614039 PMCID: PMC9130985 DOI: 10.1038/s41419-022-04961-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Revised: 05/12/2022] [Accepted: 05/17/2022] [Indexed: 12/14/2022]
Abstract
The new coronavirus SARS-CoV-2 is the causative agent of the COVID-19 pandemic, which so far has caused over 6 million deaths in 2 years, despite new vaccines and antiviral medications. Drug repurposing, an approach for the potential application of existing pharmaceutical products to new therapeutic indications, could be an effective strategy to obtain quick answers to medical emergencies. Following a virtual screening campaign on the most relevant viral proteins, we identified the drug raloxifene, a known Selective Estrogen Receptor Modulator (SERM), as a new potential agent to treat mild-to-moderate COVID-19 patients. In this paper we report a comprehensive pharmacological characterization of raloxifene in relevant in vitro models of COVID-19, specifically in Vero E6 and Calu-3 cell lines infected with SARS-CoV-2. A large panel of the most common SARS-CoV-2 variants isolated in Europe, United Kingdom, Brazil, South Africa and India was tested to demonstrate the drug's ability in contrasting the viral cytopathic effect (CPE). Literature data support a beneficial effect by raloxifene against the viral infection due to its ability to interact with viral proteins and activate protective estrogen receptor-mediated mechanisms in the host cells. Mechanistic studies here reported confirm the significant affinity of raloxifene for the Spike protein, as predicted by in silico studies, and show that the drug treatment does not directly affect Spike/ACE2 interaction or viral internalization in infected cell lines. Interestingly, raloxifene can counteract Spike-mediated ADAM17 activation in human pulmonary cells, thus providing new insights on its mechanism of action. A clinical study in mild to moderate COVID-19 patients (NCT05172050) has been recently completed. Our contribution to evaluate raloxifene results on SARS-CoV-2 variants, and the interpretation of the mechanisms of action will be key elements to better understand the trial results, and to design new clinical studies aiming to evaluate the potential development of raloxifene in this indication.
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Affiliation(s)
| | - Licia Bordi
- grid.419423.90000 0004 1760 4142National Institute for Infectious Diseases Lazzaro Spallanzani-IRCCS, Rome, Italy
| | - Giulia Matusali
- grid.419423.90000 0004 1760 4142National Institute for Infectious Diseases Lazzaro Spallanzani-IRCCS, Rome, Italy
| | | | | | | | | | - Francesca Caccuri
- grid.7637.50000000417571846Department of Molecular and Translational Medicine, Section of Microbiology and Virology, University of Brescia Medical School, Brescia, Italy
| | - Antonella Bugatti
- grid.7637.50000000417571846Department of Molecular and Translational Medicine, Section of Microbiology and Virology, University of Brescia Medical School, Brescia, Italy
| | - Alberto Zani
- grid.7637.50000000417571846Department of Molecular and Translational Medicine, Section of Microbiology and Virology, University of Brescia Medical School, Brescia, Italy
| | - Federica Filippini
- grid.7637.50000000417571846Department of Molecular and Translational Medicine, Section of Microbiology and Virology, University of Brescia Medical School, Brescia, Italy
| | - Laura Scorzolini
- grid.419423.90000 0004 1760 4142National Institute for Infectious Diseases Lazzaro Spallanzani-IRCCS, Rome, Italy
| | - Marco Gobbi
- grid.4527.40000000106678902Department of Biochemistry and Molecular Pharmacology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy
| | - Marten Beeg
- grid.4527.40000000106678902Department of Biochemistry and Molecular Pharmacology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy
| | - Arianna Piotti
- grid.4527.40000000106678902Department of Biochemistry and Molecular Pharmacology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy
| | - Monica Montopoli
- grid.5608.b0000 0004 1757 3470Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Padua, VIMM Veneto Institute Molecular Medicine, Padua, Italy
| | - Veronica Cocetta
- grid.5608.b0000 0004 1757 3470Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Padua, VIMM Veneto Institute Molecular Medicine, Padua, Italy
| | - Silvia Bressan
- grid.5608.b0000 0004 1757 3470Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Padua, VIMM Veneto Institute Molecular Medicine, Padua, Italy
| | - Enrico M. Bucci
- grid.264727.20000 0001 2248 3398Sbarro Health Research Organization, Biology Department CFT, Temple University, Philadelphia, PA USA
| | - Arnaldo Caruso
- grid.7637.50000000417571846Department of Molecular and Translational Medicine, Section of Microbiology and Virology, University of Brescia Medical School, Brescia, Italy
| | - Emanuele Nicastri
- grid.419423.90000 0004 1760 4142National Institute for Infectious Diseases Lazzaro Spallanzani-IRCCS, Rome, Italy
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8
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Kim W. Chronic Liver Disease. SEX/GENDER-SPECIFIC MEDICINE IN THE GASTROINTESTINAL DISEASES 2022:209-227. [DOI: 10.1007/978-981-19-0120-1_14] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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9
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Hu S, Yin F, Nie L, Wang Y, Qin J, Chen J. Estrogen and Estrogen Receptor Modulators: Potential Therapeutic Strategies for COVID-19 and Breast Cancer. Front Endocrinol (Lausanne) 2022; 13:829879. [PMID: 35399920 PMCID: PMC8985365 DOI: 10.3389/fendo.2022.829879] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Accepted: 02/21/2022] [Indexed: 01/08/2023] Open
Abstract
Owing to the ongoing coronavirus disease 2019 (COVID-19) pandemic, we need to pay a particular focus on the impact of coronavirus infection on breast cancer patients. Approximately 70% of breast cancer patients express estrogen receptor (ER), and intervention therapy for ER has been the primary treatment strategy to prevent the development and metastasis of breast cancer. Recent studies have suggested that selective estrogen receptor modulators (SERMs) are a potential therapeutic strategy for COVID-19. With its anti-ER and anti-viral combined functions, SERMs may be an effective treatment for COVID-19 in patients with breast cancer. In this review, we explore the latent effect of SERMs, especially tamoxifen, and the mechanism between ER and virus susceptibility.
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Affiliation(s)
- Shuying Hu
- Guangxi Health Commission Key Laboratory of Tumor Immunology and Receptor-Targeted Drug Basic Research, Guilin Medical University, Guilin, China
| | - Feiying Yin
- Guangxi Health Commission Key Laboratory of Tumor Immunology and Receptor-Targeted Drug Basic Research, Guilin Medical University, Guilin, China
- Laboratory of Environmental Pollution and Integrative Omics, Guilin Medical University, Guilin, China
| | - Litao Nie
- Laboratory of Environmental Pollution and Integrative Omics, Guilin Medical University, Guilin, China
| | - Yuqin Wang
- Laboratory of Environmental Pollution and Integrative Omics, Guilin Medical University, Guilin, China
| | - Jian Qin
- Department of Radiotherapy III, Clinical Oncology Canter, The People’s Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
- *Correspondence: Jian Qin, ; Jian Chen,
| | - Jian Chen
- Guangxi Health Commission Key Laboratory of Tumor Immunology and Receptor-Targeted Drug Basic Research, Guilin Medical University, Guilin, China
- Breast Center, the Second Affiliated Hospital of Guilin Medical University, Guilin, China
- *Correspondence: Jian Qin, ; Jian Chen,
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10
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Allegretti M, Cesta MC, Zippoli M, Beccari A, Talarico C, Mantelli F, Bucci EM, Scorzolini L, Nicastri E. Repurposing the estrogen receptor modulator raloxifene to treat SARS-CoV-2 infection. Cell Death Differ 2022; 29:156-166. [PMID: 34404919 PMCID: PMC8370058 DOI: 10.1038/s41418-021-00844-6] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 07/09/2021] [Accepted: 07/25/2021] [Indexed: 12/15/2022] Open
Abstract
The ongoing coronavirus disease 2019 (COVID-19) pandemic caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) necessitates strategies to identify prophylactic and therapeutic drug candidates to enter rapid clinical development. This is particularly true, given the uncertainty about the endurance of the immune memory induced by both previous infections or vaccines, and given the fact that the eradication of SARS-CoV-2 might be challenging to reach, given the attack rate of the virus, which would require unusually high protection by a vaccine. Here, we show how raloxifene, a selective estrogen receptor modulator with anti-inflammatory and antiviral properties, emerges as an attractive candidate entering clinical trials to test its efficacy in early-stage treatment COVID-19 patients.
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Affiliation(s)
| | | | | | | | | | | | - Enrico M Bucci
- Sbarro Health Research Organization, Biology Department CFT, Temple University, Philadelphia, PA, USA
| | - Laura Scorzolini
- Lazzaro Spallanzani National Institute for Infectious Diseases, IRCCS, Rome, Italy
| | - Emanuele Nicastri
- Lazzaro Spallanzani National Institute for Infectious Diseases, IRCCS, Rome, Italy
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11
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Marchetti G, Asmuth D. Women are from venus: implications for diversified sex-based preexposure prophylaxis approaches. AIDS 2021; 35:1691-1693. [PMID: 34270492 DOI: 10.1097/qad.0000000000002995] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Affiliation(s)
- Giulia Marchetti
- Department of Health Sciences, Clinic of infectious Diseases and Tropical Medicine, University of Milan, ASST Santi Paolo e Carlo, Milan, Italy
| | - David Asmuth
- Division of Infectious Diseases, University of California Davis Medical Center, Sacramento, CA, USA
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12
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Hong S, Chang J, Jeong K, Lee W. Raloxifene as a treatment option for viral infections. J Microbiol 2021; 59:124-131. [PMID: 33527314 PMCID: PMC7849956 DOI: 10.1007/s12275-021-0617-7] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Revised: 12/28/2020] [Accepted: 12/28/2020] [Indexed: 01/31/2023]
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused corona virus disease 2019 (COVID-19) pandemic and led to mass casualty. Even though much effort has been put into development of vaccine and treatment methods to combat COVID-19, no safe and efficient cure has been discovered. Drug repurposing or drug repositioning which is a process of investigating pre-existing drug candidates for novel applications outside their original medical indication can speed up the drug development process. Raloxifene is a selective estrogen receptor modulator (SERM) that has been approved by FDA in 1997 for treatment and prevention of postmenopausal osteoporosis and cancer. Recently, raloxifene demonstrates efficacy in treating viral infections by Ebola, influenza A, and hepatitis C viruses and shows potential for drug repurposing for the treatment of SARS-CoV-2 infection. This review will provide an overview of raloxifene's mechanism of action as a SERM and present proposed mechanisms of action in treatment of viral infections.
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Affiliation(s)
- Subin Hong
- School of Pharmacy, Sungkyunkwan University, Suwon, 16419 Republic of Korea
| | - JuOae Chang
- School of Pharmacy, Sungkyunkwan University, Suwon, 16419 Republic of Korea
| | - Kwiwan Jeong
- Bio-center, Gyeonggido Business & Science Accelerator, Suwon, 16229 Republic of Korea
| | - Wonsik Lee
- School of Pharmacy, Sungkyunkwan University, Suwon, 16419 Republic of Korea
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13
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Soni NK, Sonali LJ, Singh A, Mangla B, Neupane YR, Kohli K. Nanostructured lipid carrier potentiated oral delivery of raloxifene for breast cancer treatment. NANOTECHNOLOGY 2020; 31:475101. [PMID: 32886644 DOI: 10.1088/1361-6528/abaf81] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
Nanotherapeutics in cancer treatment are dominating global science and research, and have been recognized as the pioneering medical care regimen. Raloxifene (RLN) has been used for its anti-proliferative action on mammary tissue, however, it suffers from poor oral bioavailability. This investigation gives an account of the design and development of RLN-loaded nanostructured lipid carriers (RLN-NLCs) using a simple and scalable ultrasonication method for improved oral efficacy and limited offsite toxicity using Compritol® 888 ATO as a solid lipid and Transcutol® HP as a liquid lipid. In addition, the optimized RLN-NLCs were in the nanometric range (121 nm) with high % entrapment efficiency (%EE) (81%) for RLN, and were further freeze-dried in the presence of mannitol to enhance the stability of RLN-NLCs in the dry state for long-term use. Morphological observation under a transmission electron microscope and scanning electron microscope revealed the spherical smooth surface nanometric size of RLN-NLCs. Powder x-ray diffraction confirmed the encapsulation of RLN into the RLN-NLC's matrix with reduced crystallinity of the drug. The in vitro release study showed a burst release for an initial 4 h, and sustained release for up to 24 h. Furthermore, the RLN-NLCs showed higher cytotoxicity towards MCF-7 cells in vitro in comparison to RLN suspension, and an ex vivo intestinal permeation study demonstrated improved intestinal permeability of RLN-NLCs. Moreover, the in vivo pharmacokinetic study in female Wistar rats showed a 4.79-fold increment in oral bioavailability of RLN from RLN-NLCs compared to RLN suspension. Taken together, our results pave the way for a new nanotherapeutic approach towards breast cancer treatment.
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Affiliation(s)
- Nimrit Kaur Soni
- Department of Pharmaceutics, Delhi Pharmaceutical Sciences and Research University, New Delhi 110017, India
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14
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Pirhadi R, Sinai Talaulikar V, Onwude J, Manyonda I. Could Estrogen Protect Women From COVID-19? J Clin Med Res 2020; 12:634-639. [PMID: 33029269 PMCID: PMC7524561 DOI: 10.14740/jocmr4303] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2020] [Accepted: 09/01/2020] [Indexed: 12/12/2022] Open
Abstract
The apparent gender differences in favor of women in the risk of contracting and dying from coronavirus disease 2019 (COVID-19), and the fact that such trends have also been observed in recent epidemics including severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), have prompted the obvious question: Are the reasons life-style or biological? True, women generally make healthier lifestyle choices as compared to men. Women do not smoke or drink as much as men, and they have a lower burden of those diseases (heart disease, diabetes or chronic lung conditions) that are known to be significant factors in the higher death rates among men with COVID-19. But there is compelling evidence for a role for biological factors. Genes are likely to play an important role. The X chromosome, of which women possess two, contains the largest number of immune-related genes of the whole human genome, theoretically giving women double the advantage over men in mounting an efficient and rapid immune response. A fundamental difference between women and men is their hormonal milieu, and it is not unreasonable to suppose that the dominant female hormone estrogen could influence the response to infection. In this paper we evaluate the evidence and mechanisms by which estrogen could provide protection to women from a variety of viruses, perhaps including the coronavirus that causes COVID-19.
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Affiliation(s)
- Roxanna Pirhadi
- Faculty of Health, Education, Medicine and Social Care, Anglia Ruskin University, Second Floor William Harvey Building, Bishop Hall Lane, Chelmsford CM1 1SQ, UK
| | - Vikram Sinai Talaulikar
- Reproductive Medicine Unit, EGA Wing, University College London Hospital, 235 Euston Road, London NW1 2BU, UK
| | - Joseph Onwude
- The Chelmsford Private Day Surgery Hospital, Fenton House, 85-89 New London Road, Chelmsford CM2 0PP, UK
| | - Isaac Manyonda
- Department of Obstetrics and Gynaecology, St George's University Hospitals NHS Foundation Trust/St George's, University of London, London, UK
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15
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Garg A, Singh B, Sharma R, Singh A, Kumar A. Selective Estrogen Receptor Modulators (SERMs): Mechanistic Insights Against Microbial Infections. Curr Mol Med 2020; 20:102-115. [PMID: 31622201 DOI: 10.2174/1566524019666191014112133] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2019] [Revised: 09/06/2019] [Accepted: 09/13/2019] [Indexed: 12/31/2022]
Abstract
Background:
Infections are one of the leading causes of death worldwide
and currently available treatments remain unsatisfactory due to rise in the cases of
antimicrobial resistance. Thus, there is a need for the development of new drugs with
different mechanisms of action. However, the development of new antimicrobials agents
is a long and expensive process. Hence, most of the pharmaceutical companies are
Methodology:
The data related to SERMs and microbial infection has been extracted
from Pub Med (from January 1997 to December 2018). A total of 101 studies have been
published from 1997 -2018 regarding SERMs and microbial infections.
Results:
On the basis of inclusion and exclusion criteria, 25 studies have been included
for the analysis of level of evidence regarding antimicrobial effects of SERMs. Emerging
reports have indicated the antimicrobial property of selective estrogen receptor
modulators (SERMs) against normal and resistant strains under in vitro and in vivo
conditions against wide variety of microorganisms through different mechanisms of
action.
Conclusion:
In conclusion, SERMs could be developed as a broad spectrum
antimicrobial agent alone or in combination with existing antimicrobial agents.
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Affiliation(s)
- Aakriti Garg
- Department of Pharmacology, Indo-Soviet Friendship College of Pharmacy (ISFCP), Moga, Punjab, India
| | - Balraj Singh
- Department of Pharmacology, Indo-Soviet Friendship College of Pharmacy (ISFCP), Moga, Punjab, India
| | - Ruchika Sharma
- Department of Biotechnology, Indo-Soviet Friendship Institute of Professional Studies (ISFIPS), Moga, Punjab, India
| | - Arti Singh
- Department of Pharmacology, Indo-Soviet Friendship College of Pharmacy (ISFCP), Moga, Punjab, India
| | - Anoop Kumar
- Department of Pharmacology, Indo-Soviet Friendship College of Pharmacy (ISFCP), Moga, Punjab, India
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16
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Sexual dimorphism in hepatitis B and C and hepatocellular carcinoma. Semin Immunopathol 2018; 41:203-211. [PMID: 30498927 DOI: 10.1007/s00281-018-0727-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2018] [Accepted: 11/04/2018] [Indexed: 12/14/2022]
Abstract
The incidence of viral hepatitis B or C (HBV/HCV) infection and hepatocellular carcinoma is higher in male compared to female populations, showing a faster disease progression and results in a worse overall survival. Indeed, women are in general better protected from viral infections and show a lower risk of death from malignant cancer in comparison to men. Females mount stronger innate and adaptive immune responses than males, and therefore, most of the autoimmune diseases occur predominantly in females. Next to occupational and/or behavioral factors, cellular and molecular differences between the two sexes contribute to this observation. In this review, we will discuss underlying mechanisms that are important for the observed sex-related differences in liver diseases. A better appreciation of these differences between the two sexes might be of value for better and gender-specific treatment options.
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17
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Han M, Qi X, Bi D, Li Y, Guo Y, Wang X, Feng L. Administration of raloxifene hydrochloride nanosuspensions partially attenuates bone loss in ovariectomized mice. RSC Adv 2018; 8:23748-23756. [PMID: 35540259 PMCID: PMC9081861 DOI: 10.1039/c8ra02535e] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2018] [Accepted: 06/19/2018] [Indexed: 11/28/2022] Open
Abstract
Postmenopausal osteoporosis is a systemic skeletal disease of fragility fractures due to the loss of the mass and the deterioration of the microarchitecture of bone. This study aimed to assess the effects of raloxifene hydrochloride nanosuspensions (RLX-NSps) on ovariectomized (OVX)-induced osteoporotic rats, and the underlying mechanisms were also investigated in vivo and ex vivo. RLX-NSps were successfully prepared, and the obtained RLX-NSps had a mean particle size of (91.17 ± 0.73) nm, PDI value of 0.201 ± 0.03 and zeta potential of (36.3 ± 1.8) mV. RLX-NSps showed a clear colloidal solution with light yellow opalescence. RLX-NSps were stable in artificial intestinal fluid, artificial gastric fluid, PBS, isotonic glucose and physiological saline. The OVX mice were administered an RLX-NSps or RLX solution for 3 weeks. The bone micro-tomographic histomorphometry and bone mineral density (BMD) were assessed by micro-CT, and the biochemical markers procollagen type I N-terminal propeptide (P1NP) and beta-isomerized C-telopeptide (β-CTX) were determined from serum. Finally, primary bone marrow stromal cells (BMSCs) were isolated from the tibia and cultured to evaluate cell proliferation and osteogenic differentiation. The results demonstrated that the RLX-NSp group had a better effect on the bone microarchitecture than the RLX solution group. Therefore, RLX-NSps could partially attenuate bone loss more effectively than RLX solution in OVX mice by inhibiting bone resorption and improving the ability of BMSCs to proliferate and their osteogenic differentiation to some extent. Based on these results, nanosuspensions (NSps) may be a promising delivery system for postmenopausal osteoporosis therapy. RLX-NSps could partially attenuate bone loss more effectively than RLX solution in OVX mice by inhibiting bone resorption and improving the ability of BMSCs to proliferate and their osteogenic differentiation to some extent.![]()
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Affiliation(s)
- Meihua Han
- Institute of Medicinal Plant Development
- Chinese Academy of Medical Sciences
- Peking Union Medical College
- Beijing 100193
- China
| | - Xiaoyu Qi
- Institute of Medicinal Plant Development
- Chinese Academy of Medical Sciences
- Peking Union Medical College
- Beijing 100193
- China
| | - Dongdong Bi
- Institute of Medicinal Plant Development
- Chinese Academy of Medical Sciences
- Peking Union Medical College
- Beijing 100193
- China
| | - Yijing Li
- Institute of Medicinal Plant Development
- Chinese Academy of Medical Sciences
- Peking Union Medical College
- Beijing 100193
- China
| | - Yifei Guo
- Institute of Medicinal Plant Development
- Chinese Academy of Medical Sciences
- Peking Union Medical College
- Beijing 100193
- China
| | - Xiangtao Wang
- Institute of Medicinal Plant Development
- Chinese Academy of Medical Sciences
- Peking Union Medical College
- Beijing 100193
- China
| | - Li Feng
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital
- Chinese Academy of Medical Sciences and Peking Union Medical College
- Beijing
- China
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18
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Iyer JK, Kalra M, Kaul A, Payton ME, Kaul R. Estrogen receptor expression in chronic hepatitis C and hepatocellular carcinoma pathogenesis. World J Gastroenterol 2017; 23:6802-6816. [PMID: 29085224 PMCID: PMC5645614 DOI: 10.3748/wjg.v23.i37.6802] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2017] [Revised: 05/12/2017] [Accepted: 07/24/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate gender-specific liver estrogen receptor (ER) expression in normal subjects and patients with hepatitis C virus (HCV)-related cirrhosis and hepatocellular carcinoma (HCC).
METHODS Liver tissues from normal donors and patients diagnosed with HCV-related cirrhosis and HCV-related HCC were obtained from the NIH Liver Tissue and Cell Distribution System. The expression of ER subtypes, ERα and ERβ, were evaluated by Western blotting and real-time RT-PCR. The subcellular distribution of ERα and ERβ was further determined in nuclear and cytoplasmic tissue lysates along with the expression of inflammatory [activated NF-κB and IκB-kinase (IKK)] and oncogenic (cyclin D1) markers by Western blotting and immunohistochemistry. The expression of ERα and ERβ was correlated with the expression of activated NF-κB, activated IKK and cyclin D1 by Spearman’s correlation.
RESULTS Both ER subtypes were expressed in normal livers but male livers showed significantly higher expression of ERα than females (P < 0.05). We observed significantly higher mRNA expression of ERα in HCV-related HCC liver tissues as compared to normals (P < 0.05) and ERβ in livers of HCV-related cirrhosis and HCV-related HCC subjects (P < 0.05). At the protein level, there was a significantly higher expression of nuclear ERα in livers of HCV-related HCC patients and nuclear ERβ in HCV-related cirrhosis patients as compared to normals (P < 0.05). Furthermore, we observed a significantly higher expression of phosphorylated NF-κB and cyclin D1 in diseased livers (P < 0.05). There was a positive correlation between the expression of nuclear ER subtypes and nuclear cyclin D1 and a negative correlation between cytoplasmic ER subtypes and cytoplasmic phosphorylated IKK in HCV-related HCC livers. These findings suggest that dysregulated expression of ER subtypes following chronic HCV-infection may contribute to the progression of HCV-related cirrhosis to HCV-related HCC.
CONCLUSION Gender differences were observed in ERα expression in normal livers. Alterations in ER subtype expression observed in diseased livers may influence gender-related disparity in HCV-related pathogenesis.
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Affiliation(s)
- Janaki K Iyer
- Department of Biochemistry and Microbiology, Oklahoma State University-Center for Health Sciences, Tulsa, OK 74107, United States
- (Current Affiliation) Department of Natural Sciences, Northeastern State University, Tahlequah, OK 74464, United States
| | - Mamta Kalra
- Immatics US Inc, Houston, TX 77077, United States
| | - Anil Kaul
- Health Care Administration, Oklahoma State University-Center for Health Sciences, Tulsa, OK 74107, United States
| | - Mark E Payton
- Department of Statistics, Oklahoma State University, Stillwater, OK 74078, United States
| | - Rashmi Kaul
- Department of Biochemistry and Microbiology, Oklahoma State University-Center for Health Sciences, Tulsa, OK 74107, United States
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19
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Karampatou A, Han X, Kondili LA, Taliani G, Ciancio A, Morisco F, Critelli RM, Baraldi E, Bernabucci V, Troshina G, Guarino M, Tagliavini S, D'Ambrosio F, Bristot L, Turco L, Rosato S, Vella S, Trenti T, Neri I, La Marca A, Manthena S, Goldstein AS, Bruno S, Bao Y, Gonzalez YS, Villa E. Premature ovarian senescence and a high miscarriage rate impair fertility in women with HCV. J Hepatol 2017; 68:S0168-8278(17)32259-6. [PMID: 28882581 DOI: 10.1016/j.jhep.2017.08.019] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2017] [Revised: 08/24/2017] [Accepted: 08/27/2017] [Indexed: 01/04/2023]
Abstract
BACKGROUND & AIMS Premenopausal women who are HCV positive (HCV+) have failing ovarian function, which is likely to impact their fertility. Thus, we investigated the reproductive history, risk of infertility, and pregnancy outcomes in women of childbearing age who were HCV+. METHODS Three different groups were studied: (1) Clinical cohort: 100 women who were HCV+ and also had chronic liver disease (CLD), age matched with 50 women who were HBV+ with CLD and with 100 healthy women; all women were consecutively observed in three gastroenterology units in hospitals in Italy; (2) 1,998 women who were HCV+ and enrolled in the Italian Platform for the Study of Viral Hepatitis Therapies (PITER); (3) 6,085 women, who were mono-infected with HCV, and 20,415 women, who were HCV-, from a large de-identified insurance database from the USA. MEASUREMENTS total fertility rate (TFR) defined as the average number of children that a woman would bear during her lifetime. To define the reproductive stage of each participant, levels of anti-Müllerian hormone (AMH) and 17β-estradiol were measured. RESULTS Clinical cohort: women who were either HCV+ or HBV+ had similar CLD severity and age at first pregnancy. Based on a multivariate analysis, women who were HCV+ had a higher risk of miscarriage than those who were HBV+ (odds ratio [OR] 6,905; 95% CI 1.771-26.926). Among women who were HCV+, incidence of miscarriage was correlated with median AMH level (1.0 ng/ml). Achieving a sustained virologic response (SVR) after antiviral treatment reduced the risk of miscarriage (OR 0.255; 95% CI 0.090-0.723). In the PITER-HCV cohort, miscarriage occurred in 42.0% of women (44.6% had multiple miscarriages). TFR for women who were HCV+ and between 15 and 49 years of age was 0.7 vs. 1.37 of Italian population of the same age range. In the US cohort: compared with women who were HCV-, women who were HCV+ positive were significantly more likely to have infertility (OR 2.439; 95% CI 2.130-2.794), premature birth (OR 1.34; 95% CI 1.060-1.690), gestational diabetes (OR 1.24; 95% CI 1.020-1.510), and pre-eclampsia (OR 1.206; 95% CI 0.935-1.556), and were less likely to have a live birth (OR 0.754; 95% CI 0.622-0.913). CONCLUSIONS Ovarian senescence in women of childbearing age who are HCV+ is associated with a lower chance of live birth, greater risk of infertility, gestational diabetes, pre-eclampsia and miscarriage. Such risks could be positively influenced by successful HCV cure. LAY SUMMARY Most new cases of HCV infection are among people who inject drugs, many of whom are young women in their childbearing years. Women of reproductive age who are HCV+ display markers of ovarian senescence. This is associated with an increased burden in terms of infertility and adverse pregnancy outcomes, including stillbirth, miscarriage, fewer live births, and gestational diabetes. Early viral suppression with therapy is likely to mitigate these risks.
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Affiliation(s)
- Aimilia Karampatou
- Division of Gastroenterology, Azienda Ospedaliero-Universitaria Policlinico di Modena, University of Modena and Reggio Emilia, Modena, Italy
| | - Xue Han
- Leonard D. Schaeffer Center, University of Southern California, Los Angeles, CA, USA
| | - Loreta A Kondili
- Center for Global Health, Istituto Superiore di Sanità, Rome, Italy
| | - Gloria Taliani
- Department of Clinical Medicine, University of Rome 'La Sapienza', Rome, Italy
| | - Alessia Ciancio
- Division of Gastroenterology, University of Turin, Turin, Italy
| | - Filomena Morisco
- Department of Clinical Medicine and Surgery, Gastroenterology Unit, University of Naples 'Federico II', Naples, Italy
| | - Rosina Maria Critelli
- Division of Gastroenterology, Azienda Ospedaliero-Universitaria Policlinico di Modena, University of Modena and Reggio Emilia, Modena, Italy
| | - Enrica Baraldi
- Clinical Pathology-Toxicology, Ospedale S Agostino-Estense, Modena, Italy
| | - Veronica Bernabucci
- Division of Gastroenterology, Azienda Ospedaliero-Universitaria Policlinico di Modena, University of Modena and Reggio Emilia, Modena, Italy
| | - Giulia Troshina
- Division of Gastroenterology, University of Turin, Turin, Italy
| | - Maria Guarino
- Department of Clinical Medicine and Surgery, Gastroenterology Unit, University of Naples 'Federico II', Naples, Italy
| | | | - Federica D'Ambrosio
- Division of Gastroenterology, Azienda Ospedaliero-Universitaria Policlinico di Modena, University of Modena and Reggio Emilia, Modena, Italy
| | - Laura Bristot
- Division of Gastroenterology, Azienda Ospedaliero-Universitaria Policlinico di Modena, University of Modena and Reggio Emilia, Modena, Italy
| | - Laura Turco
- Division of Gastroenterology, Azienda Ospedaliero-Universitaria Policlinico di Modena, University of Modena and Reggio Emilia, Modena, Italy
| | - Stefano Rosato
- Center for Global Health, Istituto Superiore di Sanità, Rome, Italy
| | - Stefano Vella
- Center for Global Health, Istituto Superiore di Sanità, Rome, Italy
| | - Tommaso Trenti
- Clinical Pathology-Toxicology, Ospedale S Agostino-Estense, Modena, Italy
| | - Isabella Neri
- Obstetrics and Gynecology, Azienda Ospedaliero-Universitaria Policlinico di Modena, University of Modena and Reggio Emilia, Modena, Italy
| | - Antonio La Marca
- Obstetrics and Gynecology, Azienda Ospedaliero-Universitaria Policlinico di Modena, University of Modena and Reggio Emilia, Modena, Italy
| | | | | | - Savino Bruno
- Humanitas University and Humanitas Research Hospital Rozzano, Milan, Italy
| | | | | | - Erica Villa
- Division of Gastroenterology, Azienda Ospedaliero-Universitaria Policlinico di Modena, University of Modena and Reggio Emilia, Modena, Italy.
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Wang FP, Zhang PA, Yang XY. Relationship between sex hormones and RIG-I signaling in peripheral blood mononuclear cells of patients infected with hepatitis C virus. Exp Ther Med 2017; 14:2728-2732. [PMID: 28962219 DOI: 10.3892/etm.2017.4829] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2017] [Accepted: 07/14/2017] [Indexed: 01/22/2023] Open
Abstract
It has previously been suggested that men and women demonstrate differing immune responses to hepatitis C virus (HCV) infection, resulting in the investigation of the role of sex hormones and if they influence the anti-HCV response. The present study aimed to examine if hormone levels were associated with interferon (IFN) signaling pathways in peripheral blood mononuclear cells of 131 patients infected with HCV and 113 healthy controls. HCV infection was diagnosed based on the presence of anti-HCV antibodies and HCV RNA in serum. Expression of testosterone and estrogen was measured at the protein level using a competitive chemiluminescence immunoassay, and at the mRNA level using reverse transcription-quantitative polymerase chain reaction. HCV-infected males had increased levels of estrogen and a decreased ratio of testosterone to estrogen compared with healthy male controls (all P<0.001). HCV-infected patients demonstrated a significantly decreased expression of IFN and retinoic acid-induced gene protein I (RIG-I), RIG-I mRNA compared with controls. Pearson correlation analysis revealed that among males, levels of RIG-I correlated with levels of IFN-β mRNA (r=0.460), testosterone (r=-0.500), and the ratio of testosterone to estrogen (r=-0.477; all P<0.001). However, levels of RIG-I did not correlate with levels of IFN-α mRNA (r=0.158) or estrogen (r=0.173; both P>0.05). These results suggested that testosterone or the ratio of testosterone to estrogen may inhibit RIG-I signaling and thereby influence immune responses to HCV infection.
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Affiliation(s)
- Fang Ping Wang
- Department of Clinical Laboratory, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Ping An Zhang
- Department of Clinical Laboratory, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Xiao Yan Yang
- Department of Clinical Laboratory, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
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21
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Yamagiwa S, Ishikawa T, Waguri N, Sugitani S, Wakabayashi H, Ohkoshi S, Tsukishiro T, Takahashi T, Watanabe T, Terai S. Efficacy and safety of telaprevir- and simeprevir-based triple therapies for older patients with chronic hepatitis C. World J Hepatol 2017; 9:252-262. [PMID: 28261382 PMCID: PMC5316845 DOI: 10.4254/wjh.v9.i5.252] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2016] [Revised: 10/23/2016] [Accepted: 01/14/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluate and compare the efficacy and safety of telaprevir (TVR)-and simeprevir (SMV)-based triple therapies in elderly patients, specifically patients aged 66 years or older.
METHODS The present study enrolled 112 and 76 Japanese patients with chronic hepatitis C virus genotype 1b infection who were treated with a 12-wk TVR-based or SMV-based triple therapy, respectively, followed by a dual therapy that included pegylated interferon α and ribavirin (RBV) for 12 wk. The patients were categorized into two groups according to age as follows: A younger group of patients aged ≤ 65 years old and an older group of patients aged > 65 years old. Among the patients treated with TVR-based triple therapy, 34 patients were included in the older group. The median ages were 56 years (range: 28-65 years) in the younger group and 69 years (range: 66-81 years) in the older group. Among the patients treated with SMV-based triple therapy, 39 patients were included in the older group. The median ages were 59 years (range: 36-65 years) in the younger group and 71 years (range: 66-86 years) in the older group. The clinical, biochemical and virological data were analyzed before and during treatment.
RESULTS Among the patients treated with the TVR-based triple therapy, no significant difference in the sustained virological response (SVR) was found between the younger (80.8%) and older (88.2%) groups. The SVR rates for patients with the interleukin 28B (IL28B) (rs8099917) TG/GG-genotypes (73.9% and 60.0% in the younger and older groups, respectively) were significantly lower than for patients with the IL28B TT-genotype (86.3% and 92.9%, respectively). The cumulative exposure to RBV for the entire 24-wk treatment period (as a percentage of the target dose) was significantly higher in the younger group than in the older group (91.7% vs 66.7%, respectively, P < 0.01), but the cumulative exposure to TVR was not significantly different between the younger and older groups (91.6% vs 81.9%, respectively). A multivariate analysis identified the TT-genotype of IL28B (OR = 8.160; 95%CI: 1.593-41.804, P = 0.012) and the adherence of RBV (> 60%) (OR = 11.052; 95%CI: 1.160-105.273, P = 0.037) as independent factors associated with the SVR. Adverse events resulted in discontinuation of the treatment in 11.3% and 14.7% of the younger and older groups, respectively. Among the patients treated with the SMV-based triple therapy, no significant difference in the SVR rare was found between the younger (81.1%) and older (82.1%) groups. The SVR rates for patients with the IL28B TG/GG-genotypes (77.8% and 64.7% in the younger and older groups, respectively) were significantly lower than for patients with the IL28B TT-genotype (88.2% and 100%, respectively). A multivariate analysis identified the TT-genotype of IL28B as an independent factor associated with the SVR (OR = 9.677; 95%CI: 1.114-84.087, P = 0.040). Adverse events resulted in discontinuation of the treatment in 7.0% and 14.3% of patients in the younger and older groups, respectively.
CONCLUSION Both TVR- and SMV-based triple therapies can be successfully used to treat patients aged 66 years or older with genotype 1b chronic hepatitis C. Genotyping of the IL28B indicates a potential to achieve SVR in these difficult-to-treat elderly patients.
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22
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Biver E, Calmy A, Rizzoli R. Bone health in HIV and hepatitis B or C infections. Ther Adv Musculoskelet Dis 2017; 9:22-34. [PMID: 28101146 PMCID: PMC5228639 DOI: 10.1177/1759720x16671927] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Chronic infections with human immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV) add to age-dependent bone loss and may contribute to lower bone strength in the elderly. In this review, we report recent highlights on the epidemiology of bone fragility in chronic viral infections with HIV, HCV and HBV, its physiopathology and discuss the interference of antiviral therapies with bone metabolism. Chronic infections influence bone through the interactions between risk factors for bone fragility and falls (which are highly prevalent in infected patients), virus activity and antiviral drugs. HIV-infected patients are at increased risk of fracture and the risk is higher in cases of co-infection with HIV and untreated chronic viral hepatitis. In HIV patients, the majority of bone loss occurs during virus activity and at initiation of antiretroviral therapy (ART). However, long-term elderly HIV-infected patients on successful ART display bone microstructure alterations only partially captured by dual energy X-ray absorptiometry (DXA). Bone loss is associated with an increase of bone resorption, reflecting the upregulation of the receptor activator of nuclear factor-kappaB ligand (RANKL) and osteoprotegerin (OPG) pathways via a crosstalk between virus activity, inflammation and the immune system. The use of some antiviral drugs, such as tenofovir (controlling both HBV and HIV infections) or protease inhibitors, may be associated with higher bone toxicity. The reduction of tenofovir plasma concentrations with the implementation of tenofovir alafenamide (TAF) attenuates bone mineral density (BMD) loss but it remains unknown whether it will contribute to reducing fracture risk in long-term HIV-treated patients. Moreover, to what extent the new direct-acting agents for treatment of HCV, including nucleotide inhibitors and protease inhibitors, may affect bone health similarly as ART in HIV should be investigated.
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Affiliation(s)
- Emmanuel Biver
- Division of Bone Diseases, Department of Internal Medicine Specialties, Geneva University Hospitals and Faculty of Medicine, Rue Gabrielle-Perret-Gentil 4, 1211 Geneva 14, Switzerland
| | - Alexandra Calmy
- Division of Infectious Diseases, HIV Unit, Department of Internal Medicine Specialties, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland
| | - René Rizzoli
- Division of Bone Diseases, Department of Internal Medicine Specialties, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland
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23
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Ikezaki H, Furusyo N, Hiramine S, Ura K, Mitsumoto-Kaseida F, Takayama K, Shimizu M, Toyoda K, Ogawa E, Kainuma M, Murata M, Hayashi J. Association of IL28B rs8099917 genotype and female sex with spontaneous clearance of hepatitis C virus infection: a Japanese cross-sectional study. Arch Virol 2016; 161:641-8. [PMID: 26660164 DOI: 10.1007/s00705-015-2703-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2015] [Accepted: 11/24/2015] [Indexed: 12/20/2022]
Abstract
Hepatitis C virus (HCV) infection is a serious global health problem. Previous studies have suggested that the interleukin 28B (IL28B) rs8099917 genotype is related to spontaneous clearance of HCV in Caucasian populations. Our objective was to investigate the association of the IL28B rs8099917 genotype with spontaneous clearance of HCV by community-dwelling Japanese. A cross-sectional community-based population study of 993 Japanese residents was conducted. Based on anti-HCV antibody and HCV RNA levels, 50 subjects were assigned to the spontaneous-clearance group, 155 to the chronic-infection group, and 788 to the control group. Logistic regression analysis was done to examine the roles of the IL28B rs8099917 genotype and sex. To analyze the interactions between these factors, an "IL28B rs809991 genotype × sex" interaction term was included in the multivariate analysis. Significantly more subjects in the spontaneous-clearance group than in the chronic-infection group had the favorable IL28B rs8099917 genotype and were female. Multivariate logistic regression analysis extracted the favorable IL28B rs8099917 TT genotype (odds ratio [OR] 9.39; 95% confidence interval [CI], 2.16-40.83, P = 0.003) and female sex (OR, 2.27; 95% CI, 1.16-4.45, P = 0.017) as factors contributing to the spontaneous clearance of HCV. No significant interaction was found between the IL28B rs8099917 genotype and sex (P for interaction = 0.428). Both the favorable IL28B rs8099917 genotype and female sex were associated with the spontaneous clearance of HCV in this Japanese population.
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Affiliation(s)
- Hiroaki Ikezaki
- Department of General Internal Medicine, Kyushu University Hospital, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 8128582, Japan.
- Nutritional Epidemiology Program, Jean Mayor USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA, 02111, USA.
| | - Norihiro Furusyo
- Department of General Internal Medicine, Kyushu University Hospital, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 8128582, Japan.
| | - Satoshi Hiramine
- Department of General Internal Medicine, Kyushu University Hospital, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 8128582, Japan
| | - Kazuya Ura
- Department of General Internal Medicine, Kyushu University Hospital, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 8128582, Japan
| | - Fujiko Mitsumoto-Kaseida
- Department of General Internal Medicine, Kyushu University Hospital, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 8128582, Japan
| | - Koji Takayama
- Department of General Internal Medicine, Kyushu University Hospital, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 8128582, Japan
| | - Motohiro Shimizu
- Department of General Internal Medicine, Kyushu University Hospital, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 8128582, Japan
| | - Kazuhiro Toyoda
- Department of General Internal Medicine, Kyushu University Hospital, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 8128582, Japan
| | - Eiichi Ogawa
- Department of General Internal Medicine, Kyushu University Hospital, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 8128582, Japan
| | - Mosaburo Kainuma
- Department of General Internal Medicine, Kyushu University Hospital, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 8128582, Japan
| | - Masayuki Murata
- Department of General Internal Medicine, Kyushu University Hospital, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 8128582, Japan
| | - Jun Hayashi
- Kyushu General Internal Medicine Center, Hara-Doi Hospital, Fukuoka, 8138588, Japan
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Peretz J, Pekosz A, Lane AP, Klein SL. Estrogenic compounds reduce influenza A virus replication in primary human nasal epithelial cells derived from female, but not male, donors. Am J Physiol Lung Cell Mol Physiol 2016; 310:L415-25. [PMID: 26684252 PMCID: PMC4773846 DOI: 10.1152/ajplung.00398.2015] [Citation(s) in RCA: 65] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2015] [Accepted: 12/11/2015] [Indexed: 11/22/2022] Open
Abstract
Influenza causes an acute infection characterized by virus replication in respiratory epithelial cells. The severity of influenza and other respiratory diseases changes over the life course and during pregnancy in women, suggesting that sex steroid hormones, such as estrogens, may be involved. Using primary, differentiated human nasal epithelial cell (hNEC) cultures from adult male and female donors, we exposed cultures to the endogenous 17β-estradiol (E2) or select estrogen receptor modulators (SERMs) and then infected cultures with a seasonal influenza A virus (IAV) to determine whether estrogenic signaling could affect the outcome of IAV infection and whether these effects were sex dependent. Estradiol, raloxifene, and bisphenol A decreased IAV titers in hNECs from female, but not male, donors. The estrogenic decrease in viral titer was dependent on the genomic estrogen receptor-2 (ESR2) as neither genomic ESR1 nor nongenomic GPR30 was expressed in hNEC cultures and addition of the genomic ER antagonist ICI 182,780 reversed the antiviral effects of E2. Treatment of hNECs with E2 had no effect on interferon or chemokine secretion but significantly downregulated cell metabolic processes, including genes that encode for zinc finger proteins, many of which contain estrogen response elements in their promoters. These data provide novel insights into the cellular and molecular mechanisms of how natural and synthetic estrogens impact IAV infection in respiratory epithelial cells derived from humans.
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Affiliation(s)
- Jackye Peretz
- W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
| | - Andrew Pekosz
- W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland; Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
| | - Andrew P Lane
- Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Sabra L Klein
- W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland; Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland; and
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Ogawa E, Furusyo N, Kajiwara E, Nomura H, Kawano A, Takahashi K, Dohmen K, Satoh T, Azuma K, Nakamuta M, Koyanagi T, Kotoh K, Shimoda S, Hayashi J. Comparative effectiveness and safety study of triple therapy with simeprevir or telaprevir for non-cirrhotic patients with chronic hepatitis C virus genotype 1b infection. J Gastroenterol Hepatol 2015; 30:1759-67. [PMID: 26095167 DOI: 10.1111/jgh.13016] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2015] [Revised: 05/03/2015] [Accepted: 05/10/2015] [Indexed: 12/17/2022]
Abstract
BACKGROUND AND AIM The addition of hepatitis C virus (HCV) NS3/4A protease inhibitors to pegylated-interferon alpha (PEG-IFNα) and ribavirin (triple therapy) has greatly improved treatment outcome. The aim of this study was to compare the effectiveness and safety of simeprevir-based or telaprevir-based triple therapy for non-cirrhotic patients in real-world clinical practice. METHODS This multicenter study consisted of 835 consecutive Japanese HCV genotype 1b patients treated in a clinical setting, 716 of whom were enrolled (simeprevir = 256 and telaprevir = 460). Logistic regression was carried out after propensity score matching to assess the sustained virological response at week 12 after the end of treatment (SVR12). RESULTS In the propensity-matched cohort (253 matched pairs), the SVR12 rates of the patients who underwent simeprevir-based or telaprevir-based triple therapy were 85.0% and 84.2%, respectively, by intention-to-treat analysis. Prior treatment response to PEG-IFNα/ribavirin and IL28B genotype was independently associated with SVR12 in both groups. No significant differences in the SVR12 rates stratified by prior treatment response to PEG-IFNα/ribavirin were found between the simeprevir (treatment-naïve 89.1%, prior relapse 94.3%, prior partial response 65.0%, and prior null response 33.3%) and telaprevir (treatment-naïve 87.8%, prior relapse 90.1%, prior partial response 68.4%, and prior null response 50.0%) groups. The incidence of adverse effects, such as anemia, severe rash, and the elevation of serum creatinine, was markedly higher in the telaprevir group. CONCLUSIONS Considering the effectiveness and safety, simeprevir-based triple therapy will continue to be a useful treatment option in Japan for treatment-naïve or prior relapse patients with a favorable IL28B genotype.
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Affiliation(s)
- Eiichi Ogawa
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
| | - Norihiro Furusyo
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
| | - Eiji Kajiwara
- Department of Hepatology, Steel Memorial Yawata Hospital, Kitakyushu, Japan
| | - Hideyuki Nomura
- The Center for Liver Disease, Shin-Kokura Hospital, Kitakyushu, Japan
| | - Akira Kawano
- Department of Medicine, Kitakyushu Municipal Medical Center, Kitakyushu, Japan
| | | | - Kazufumi Dohmen
- Department of Internal Medicine, Chihaya Hospital, Fukuoka, Japan
| | - Takeaki Satoh
- Center for Liver Disease, National Hospital Organization Kokura Medical Center, Kitakyushu, Japan
| | - Koichi Azuma
- Department of Medicine, Kyushu Central Hospital, Fukuoka, Japan
| | - Makoto Nakamuta
- Department of Gastroenterology, Kyushu Medical Center, National Hospital Organization, Fukuoka, Japan
| | | | - Kazuhiro Kotoh
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Shinji Shimoda
- Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Jun Hayashi
- Kyushu General Internal Medicine Center, Haradoi Hospital, Fukuoka, Japan
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Luo F, Ishigami M, Achiwa K, Ishizu Y, Kuzuya T, Honda T, Hayashi K, Ishikawa T, Katano Y, Goto H. Raloxifene Ameliorates Liver Fibrosis of Nonalcoholic Steatohepatitis Induced by Choline-Deficient High-Fat Diet in Ovariectomized Mice. Dig Dis Sci 2015; 60:2730-9. [PMID: 25868633 DOI: 10.1007/s10620-015-3660-6] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2014] [Accepted: 04/03/2015] [Indexed: 12/15/2022]
Abstract
BACKGROUND AND AIM The prevalence of nonalcoholic fatty liver disease (NAFLD) is higher in men than in women, but according to some epidemiological studies, this gender difference disappears after menopause. Estrogen therapy protects against NAFLD and nonalcoholic steatohepatitis (NASH) after menopause. We investigated the therapeutic effect of raloxifene, a second-generation selective estrogen-receptor modulator, on NASH induced by a choline-deficient high-fat (CDHF) diet in female ovariectomized (OVX) mice. METHODS Seven-week-old female C57BL/6J mice were divided into three experimental groups as follows: (1) sham operation (SHAM group), (2) ovariectomy (OVX group), and (3) ovariectomy + raloxifene (intraperitoneal injection, 3 mg/kg body weight/day; OVX + RLX group). These three groups of mice were fed a CDHF diet for 8 weeks; choline-sufficient high-fat (CSHF) diet was used as control diet. Serum biochemical indicators of hepatic function and liver histological changes were evaluated. RESULTS Compared with CSHF diet, ovariectomy enhances liver injury and fibrosis in CDHF diet-fed mice. Serum alanine aminotransferase (ALT) levels were significantly lower in the OVX + RLX group than in the OVX group. The OVX group developed extensive steatosis with inflammation and fibrosis. Lobular inflammatory scores and fibrosis staging in the OVX + RLX group were significantly lower than in the OVX group. Furthermore, the OVX + RLX group exhibited significantly higher expression of hepatic estrogen receptor-α, which was significantly lower in the OVX group than in the SHAM group. CONCLUSIONS Raloxifene may ameliorate progression of liver fibrosis of NASH induced by CDHF diet in ovariectomized female mice, and up-regulation of estrogen receptor-α may play an important role in the beneficial effects of raloxifene on NASH.
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Affiliation(s)
- Fangqiong Luo
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan,
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Female Sex Hormones Pattern and Its Relation to Disease Severity and Treatment in Pre- and Postmenopausal Patients with Chronic Hepatitis C Virus (Genotype 4) Infection. Int J Chronic Dis 2015; 2015:927974. [PMID: 26464874 PMCID: PMC4590939 DOI: 10.1155/2015/927974] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2015] [Revised: 08/04/2015] [Accepted: 08/05/2015] [Indexed: 01/09/2023] Open
Abstract
Chronic hepatitis C (CHC) course revealed differences between men and women. Male gender and postmenopausal women are thought to be of the critical factors affecting HCV infection progression. The study aimed to assess female sex hormones and their relation to disease severity and treatment in HCV infected females. Subjects were divided to 2 groups: 44 CHC female patients and 44 controls. Both groups were classified to premenopausal and postmenopausal females. Serum estradiol (E2), progesterone (PRG), and total testosterone (TT) were assessed using chemiluminescent immunoassay. Our results showed that menopausal patients had significantly higher levels of estradiol, total testosterone, and progesterone compared to controls (P < 0.001). Reproductive aged patients had lower level of total testosterone compared to menopausal patients (P < 0.001). HCV infected females of reproductive age had higher level of progesterone compared to menopausal HCV infected females (P = 0.0014). Indicators of disease severity and treatment response were significantly worse in menopausal women compared to reproductive aged women (fibrosis: P < 0.001, activity: P = 0.045, and treatment: P < 0.001). We observed that lower estradiol level may be related to fibrosis severity in CHC females. Higher total testosterone and progesterone levels may be related to fibrosis severity and poor response to treatment in CHC menopausal females only.
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Abstract
Although not a classical target for estrogens, the liver is a target for their action and is sensitive to their deprivation. The occurrence of menopause is accompanied by a chain of events depending on the progressive estrogen deprivation that eventually leads to a shift from a low inflammatory to a high inflammatory state. This has a series of well-known consequences in many different organs and tissues (bone, heart, brain, body fat etc.) among which the liver is particularly interesting. The consequences are extremely evident in HCV-positive women in whom HCV infection and menopause cooperate to induce higher necro-inflammatory features, increased hepatic steatosis and eventually faster progression of fibrosis. In addition, menopause is the strongest negative factor for sustained viral response (SVR) in HCV-positive females, especially HCV genotype 1 (in whom menopause was the only independent factor for failure of antiviral therapy). This suggests that HCV-positive women should be treated early during fertile age to obtain maximal response to antiviral therapy.
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Affiliation(s)
- Veronica Bernabucci
- Division of Gastroenterology, Azienda Ospedaliero-Universitaria Policlinico di Modena, Università degli Studi di Modena e Reggio Emilia , Modena , Italy
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Cengiz M, Ozenirler S, Yılmaz G. Estrogen receptor alpha expression and liver fibrosis in chronic hepatitis C virus genotype 1b: a clinicopathological study. HEPATITIS MONTHLY 2014; 14:e21885. [PMID: 25368658 PMCID: PMC4214133 DOI: 10.5812/hepatmon.21885] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/09/2014] [Revised: 09/06/2014] [Accepted: 09/07/2014] [Indexed: 12/11/2022]
Abstract
BACKGROUND Hepatic damage due to chronic hepatitis C virus (HCV) genotype 1b infection varies widely. OBJECTIVES We aimed to investigate whether estrogen receptor alpha (ERα) plays a role in liver fibrosis in patients infected with HCV genotype 1b. PATIENTS AND METHODS All the consecutive patients who received the same standard treatment protocol for HCV genotype 1b were subdivided into two subgroups according to their fibrosis scores as fibrotic stages < 2 in mild fibrosis group and fibrotic stages ≥ 2 in advanced fibrosis group, depending on the presence of septal fibrosis. ERα was stained in liver biopsy specimens. Demographics and clinical properties were compared between the groups. Multivariate logistic regression analysis was performed to predict advanced fibrosis. RESULTS There were 66 patients in the mild fibrosis group and 24 in the advanced fibrosis group. Among the mild and advanced fibrosis groups, 65.1% and 50%were female, respectively (P = 0.19). There was an inverse correlation between ERα and fibrotic stage (r: -0.413; P < 0.001). Age, platelet counts, neutrophil counts, Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), Gamma glutamyl transferase (GGT) and ERα were statistically significant in the univariate analysis. In multivariate logistic regression analyses, ERα expression continued to be an independent predicting factor of liver fibrosis in patients infected with chronic HCV genotype 1b (OR: 0.10; 95% CI: 0.018-0.586; P < 0.001). CONCLUSIONS ERα expression in liver was inversely correlated with liver fibrosis among patients infected with chronic HCV genotype 1b.
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Affiliation(s)
- Mustafa Cengiz
- Department of Gastroenterology, Dr. A.Y. Ankara Oncology Training and Research Hospital, Ankara, Turkey
- Corresponding Author: Mustafa Cengiz, Department of Gastroenterology, Dr. A.Y. Ankara Oncology Training and Research Hospital, Ankara, Turkey. Tel: +90-3123360909, Fax: +90-31233403 52, E-mail:
| | - Seren Ozenirler
- Department of Gastroenterology, Faculty of Medicine, Gazi University, Ankara, Turkey
| | - Guldal Yılmaz
- Deparment of Pathology, Faculty of Medicine, Gazi University, Ankara, Turkey
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Ogawa E, Furusyo N, Nakamuta M, Kajiwara E, Nomura H, Dohmen K, Takahashi K, Satoh T, Azuma K, Kawano A, Tanabe Y, Kotoh K, Shimoda S, Akahoshi T, Maehara Y, Hayashi J. Efficacy and safety of splenectomy in telaprevir-based triple therapy for chronic hepatitis C patients with thrombocytopenia and advanced fibrosis. J Gastroenterol Hepatol 2014; 29:1728-35. [PMID: 24731162 DOI: 10.1111/jgh.12619] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/22/2014] [Indexed: 12/30/2022]
Abstract
BACKGROUND AND AIM Thrombocytopenia (TCP) of chronic hepatitis C patients with cirrhosis has a negative impact on the management of interferon-based treatment. The aim of this study is to evaluate the efficacy and safety of telaprevir-based triple therapy for patients who have undergone splenectomy (Spx). METHODS This prospective, multicenter study consisted of 80 patients, including 32 Spx and 48 non-Spx/TCP (platelet count: 60-99 × 10(9) /L) patients with advanced fibrosis infected with hepatitis C virus genotype 1b. All received 12 weeks of telaprevir in combination with 24 weeks of pegylated interferon (PEG-IFN) α2b and ribavirin. RESULTS The sustained virological response (SVR) rate of the Spx group (75.0%) was significantly higher than that of the non-Spx/TCP group (52.1%) (P < 0.05). Under favorable conditions such as treatment-naïve/prior relapse and interleukin-28B (IL28B) TT allele (rs8099917), the SVR rates of the Spx group were significantly higher than those of the non-Spx/moderate TCP (60-79 × 10(9) /L) groups (91.3% vs 50.0% and 93.8% vs 37.5%, respectively; both P < 0.05). Adequate PEG-IFNα2b adherence was associated with SVR. However, the percentage of patients who achieved 80% adherence to PEG-IFNα2b in the non-Spx/moderate TCP (42.9%) group was significantly lower than that of the Spx (79.3%) and non-Spx/mild TCP (80-99 × 10(9) /L) (80.0%) groups. Treatment discontinuation due to adverse effects and the development of bacterial infection did not differ between the Spx and non-Spx/TCP groups. CONCLUSION The increase of platelet count after Spx contributed to treatment success, especially for moderate to severe TCP patients who are treatment-naïve/prior relapse or IL28B TT allele.
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Affiliation(s)
- Eiichi Ogawa
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
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Baden R, Rockstroh JK, Buti M. Natural history and management of hepatitis C: does sex play a role? J Infect Dis 2014; 209 Suppl 3:S81-5. [PMID: 24966194 DOI: 10.1093/infdis/jiu057] [Citation(s) in RCA: 83] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Hepatitis C virus infection is a disease that disproportionately affects men more than women. After initial HCV infection, women are more likely to clear the virus spontaneously. Women also have slower rates of liver disease progression than men if they become chronically infected. However, this rate of disease progression changes over time in women. Postmenopausal women have increased rates of fibrosis compared with women of reproductive age because they have lost the protective effects of estrogen. Estradiol and estrogen receptors in the liver protect hepatocytes from oxidative stress, inflammatory injury, and cell death, which all contribute to fibrosis. As a consequence of the overall slower liver disease progression and increased viral clearance in women, the disease burden from HCV infection is found predominantly in men. Although some studies have suggested higher sustained virologic response rates in HCV-infected women receiving dual therapy for HCV infection, this seems to be less important in the direct-acting antiviral era, when response rates for HCV therapy have increased so substantially that baseline demographic factors seem to have less of an effect on overall rates of cure.
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Affiliation(s)
- Rachel Baden
- Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts
| | | | - Maria Buti
- Hospital Universitario Valle Hebron and Ciberehd del Instituto Carlos III. Barcelona, Spain
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Mingorance L, Friesland M, Coto-Llerena M, Pérez-del-Pulgar S, Boix L, López-Oliva JM, Bruix J, Forns X, Gastaminza P. Selective inhibition of hepatitis C virus infection by hydroxyzine and benztropine. Antimicrob Agents Chemother 2014; 58:3451-60. [PMID: 24709263 PMCID: PMC4068423 DOI: 10.1128/aac.02619-14] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2014] [Accepted: 04/02/2014] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) infection is a major biomedical problem worldwide as it causes severe liver disease in millions of humans around the world. Despite the recent approval of specific drugs targeting HCV replication to be used in combination with alpha interferon (IFN-α) and ribavirin, there is still an urgent need for pangenotypic, interferon-free therapies to fight this genetically diverse group of viruses. In this study, we used an unbiased screening cell culture assay to interrogate a chemical library of compounds approved for clinical use in humans. This system enables identifying nontoxic antiviral compounds targeting every aspect of the viral life cycle, be the target viral or cellular. The aim of this study was to identify drugs approved for other therapeutic applications in humans that could be effective components of combination therapies against HCV. As a result of this analysis, we identified 12 compounds with antiviral activity in cell culture, some of which had previously been identified as HCV inhibitors with antiviral activity in cell culture and had been shown to be effective in patients. We selected two novel HCV antivirals, hydroxyzine and benztropine, to characterize them by determining their specificity and genotype spectrum as well as by defining the step of the replication cycle targeted by these compounds. We found that both compounds effectively inhibited viral entry at a postbinding step of genotypes 1, 2, 3, and 4 without affecting entry of other viruses.
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Affiliation(s)
- Lidia Mingorance
- Centro Nacional De Biotecnología-Consejo Superior de Investigaciones Científicas (CNB-CSIC), Madrid, Spain
| | - Martina Friesland
- Centro Nacional De Biotecnología-Consejo Superior de Investigaciones Científicas (CNB-CSIC), Madrid, Spain
| | | | | | - Loreto Boix
- Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, Hospital Clínic, IDIBAPS, CIBERehd, Barcelona, Spain
| | - Juan Manuel López-Oliva
- Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, Hospital Clínic, IDIBAPS, CIBERehd, Barcelona, Spain
| | - Jordi Bruix
- Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, Hospital Clínic, IDIBAPS, CIBERehd, Barcelona, Spain
| | - Xavier Forns
- Liver Unit, Hospital Clinic, IDIBAPS, CIBERehd, Barcelona, Spain
| | - Pablo Gastaminza
- Centro Nacional De Biotecnología-Consejo Superior de Investigaciones Científicas (CNB-CSIC), Madrid, Spain
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Ma WL, Lai HC, Yeh S, Cai X, Chang C. Androgen receptor roles in hepatocellular carcinoma, fatty liver, cirrhosis and hepatitis. Endocr Relat Cancer 2014; 21:R165-82. [PMID: 24424503 PMCID: PMC4165608 DOI: 10.1530/erc-13-0283] [Citation(s) in RCA: 116] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Androgen/androgen receptor (AR) signaling plays important roles in normal liver function and in progression of liver diseases. In studies of noncancerous liver diseases, AR knockout mouse models of liver disease have revealed that androgen/AR signaling suppresses the development of steatosis, virus-related hepatitis, and cirrhosis. In addition, studies have shown that targeting AR in bone marrow-derived mesenchymal stem cells (BM-MSCs) improves their self-renewal and migration potentials, thereby increasing the efficacy of BM-MSC transplantation as a way to control the progression of cirrhosis. Androgen/AR signaling is known to be involved in the initiation of carcinogen- or hepatitis B virus-related hepatocellular carcinoma (HCC). However, studies have demonstrated that AR, rather than androgen, plays the dominant role in cancer initiation. Therefore, targeting AR might be an appropriate therapy for patients with early-stage HCC. In contrast, androgen/AR signaling has been shown to suppress metastasis of HCC in patients with late-stage disease. In addition, there is evidence that therapy comprising Sorafenib and agents that enhance the functional expression of AR may suppress the progression of late-stage HCC.
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Affiliation(s)
- Wen-Lung Ma
- Sex Hormone Research Center, Department of
Gastroenterology, and Graduate Institute of Clinical Medical Science, China Medical
University/Hospital, Taichung 404, Taiwan
- George Whipple Lab for Cancer Research, Departments of
Pathology and Urology and The Wilmot Cancer Center, University of Rochester Medical
Center, Rochester, NY 14642, USA
| | - Hsueh-Chou Lai
- Sex Hormone Research Center, Department of
Gastroenterology, and Graduate Institute of Clinical Medical Science, China Medical
University/Hospital, Taichung 404, Taiwan
| | - Shuyuan Yeh
- George Whipple Lab for Cancer Research, Departments of
Pathology and Urology and The Wilmot Cancer Center, University of Rochester Medical
Center, Rochester, NY 14642, USA
| | - Xiujun Cai
- Department of General Surgery, Chawnshang Chang Liver
Cancer Center, Sir Run-run Shaw Hospital, Zhejiang University, Hangzhou, China
- Corresponding author: Chawnshang
Chang () and Xiujun Cai
()
| | - Chawnshang Chang
- Sex Hormone Research Center, Department of
Gastroenterology, and Graduate Institute of Clinical Medical Science, China Medical
University/Hospital, Taichung 404, Taiwan
- George Whipple Lab for Cancer Research, Departments of
Pathology and Urology and The Wilmot Cancer Center, University of Rochester Medical
Center, Rochester, NY 14642, USA
- Corresponding author: Chawnshang
Chang () and Xiujun Cai
()
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Murata M, Furusyo N, Ogawa E, Mitsumoto F, Hiramine S, Ikezaki H, Takayama K, Shimizu M, Toyoda K, Kainuma M, Hayashi J. A case of successful hepatitis C virus eradication by 24 weeks of telaprevir-based triple therapy for a hemophilia patient with hepatitis C virus/human immunodeficiency virus co-infection who previously failed pegylated interferon-α and ribavirin therapy. J Infect Chemother 2014; 20:320-4. [PMID: 24477330 DOI: 10.1016/j.jiac.2013.11.006] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2013] [Revised: 09/25/2013] [Accepted: 11/01/2013] [Indexed: 01/13/2023]
Abstract
In Japan, the human immunodeficiency virus (HIV) and hepatitis C virus (HCV) coinfection of some patients with hemophilia was caused by the transfusion of imported blood products, such as unheated coagulation factor. With the development of antiretroviral therapy (ART) for HIV, chronic HCV infection has become a major cause of liver disease and mortality for hemophiliac patients coinfected with HCV/HIV. Data is limited regarding the efficacy and safety of antiviral therapy with the HCV protease inhibitor telaprevir (TVR) in combination with pegylated interferon-α (PegIFN-α) and ribavirin (RBV) for hemophilia patients coinfected with HCV/HIV. We report a case of a Japanese patient with hemophilia and HCV/HIV coinfection who had partial response to prior to PegIFN-α and RBV therapy. This is the first published report of 24-week TVR-based triple therapy for a hemophilia patient coinfected with HCV/HIV. The patient had HCV genotype 1a infection with a high viral load. His single-nucleotide polymorphism of the interleukin 28B (rs8099917) gene was the TT major allele. He presented with undetectable HIV RNA and a high CD4(+) T cell counts by taking ART including tenofovir, emtricitabine and raltegravir. He was again treated for HCV with TVR plus PegIFN-α2b and RBV for the first 12 weeks, followed by the continuation of PegIFN-α2b and RBV for 12 additional weeks while continuing ART. He had rapid virological response and achieved sustained virological response with the 24-week treatment. No serious adverse events such as skin rash, severe anemia or exacerbated bleeding tendency were observed, only a mild headache. No dose adjustment was necessary when tenofovir and raltegravir were used in combined with TVR, and no HIV breakthrough was observed. TVR-based triple therapy with ART could can an effective treatment for hemophilia patients coinfected with HCV (genotype 1)/HIV regardless of prior response. TVR can be used in combination with tenofovir, emtricitabine and raltegravir for patients with hemophilia. Furthermore, patients with undetectable HCV RNA at week 4 could be successfully treated with a 24-week regimen.
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Affiliation(s)
- Masayuki Murata
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan.
| | - Norihiro Furusyo
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
| | - Eiichi Ogawa
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
| | - Fujiko Mitsumoto
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
| | - Satoshi Hiramine
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
| | - Hiroaki Ikezaki
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
| | - Koji Takayama
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
| | - Motohiro Shimizu
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
| | - Kazuhiro Toyoda
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
| | - Mosaburo Kainuma
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
| | - Jun Hayashi
- Center of Kyushu General Medicine, Haradoi Hospital, Fukuoka, Japan
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Ogawa E, Furusyo N, Kajiwara E, Nomura H, Dohmen K, Takahashi K, Nakamuta M, Satoh T, Azuma K, Kawano A, Tanabe Y, Kotoh K, Shimoda S, Hayashi J. Influence of low-density lipoprotein cholesterol on virological response to telaprevir-based triple therapy for chronic HCV genotype 1b infection. Antiviral Res 2014; 104:102-9. [PMID: 24462955 DOI: 10.1016/j.antiviral.2014.01.004] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2013] [Revised: 01/06/2014] [Accepted: 01/12/2014] [Indexed: 12/12/2022]
Abstract
Elevated serum low-density lipoprotein cholesterol (LDL-C) level has been associated with sustained virological response (SVR) by chronic hepatitis C patients treated with pegylated-interferon (PEG-IFN) α and ribavirin (RBV). The aim of this study was to investigate the relation between the baseline LDL-C level and the treatment outcome from telaprevir (TVR)-based triple therapy. This prospective, multicenter study consisted of 241 treatment-experienced patients infected with HCV genotype 1b. All received 12 weeks of TVR in combination with 24 weeks of PEG-IFNα2b and RBV. The SVR rate was 81.3% (196 of 241) by intention-to-treat analysis. Higher LDL-C level was strongly associated with SVR (P=1.3×10⁻⁸). The area under the receiver operating characteristic curve for predicting SVR was 0.78 and the cutoff value for the LDL-C level at baseline was 95 mg/dL. In multivariable logistic regression analysis of predictors of SVR, LDL-C ≥95 mg/dL (odds ratio [OR] 3.60, P=0.0238), α-fetoprotein ≤5.0 ng/mL (OR 5.06, P=0.0060), prior relapse to PEG-IFNα and RBV (OR 5.71, P=0.0008), and rapid virological response (HCV RNA undetectable at week 4) (OR 5.52, P=0.0010) were extracted as independent predictors of SVR. For prior partial and null responders, the SVR rates of the groups with LDL-C ≥95 mg/dL were significantly higher than those of the <95 mg/dL groups with IL28B TG/GG and pretreatment platelet count <150×10⁹/L (both P<0.05). The baseline LDL-C level exerted a potent influence on the SVR of treatment-experienced patients treated with TVR-based triple therapy, especially for prior partial and null responders to PEG-IFNα and RBV.
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Affiliation(s)
- Eiichi Ogawa
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
| | - Norihiro Furusyo
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
| | - Eiji Kajiwara
- Department of Hepatology, Steel Memorial Yawata Hospital, Kitakyushu, Japan
| | - Hideyuki Nomura
- The Center for Liver Disease, Shin-Kokura Hospital, Kitakyushu, Japan
| | - Kazufumi Dohmen
- Department of Internal Medicine, Chihaya Hospital, Fukuoka, Japan
| | | | - Makoto Nakamuta
- Department of Gastroenterology, Kyushu Medical Center, National Hospital Organization, Fukuoka, Japan
| | - Takeaki Satoh
- Center for Liver Disease, National Hospital Organization Kokura Medical Center, Kitakyushu, Japan
| | - Koichi Azuma
- Department of Medicine, Kyushu Central Hospital, Fukuoka, Japan
| | - Akira Kawano
- Department of Medicine, Kitakyushu Municipal Medical Center, Kitakyushu, Japan
| | - Yuichi Tanabe
- Department of Medicine, Fukuoka City Hospital, Fukuoka, Japan
| | - Kazuhiro Kotoh
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Shinji Shimoda
- Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Jun Hayashi
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan.
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Ogawa E, Furusyo N, Shimizu M, Ihara T, Hayashi T, Harada Y, Toyoda K, Murata M, Hayashi J. Non-invasive fibrosis assessment predicts sustained virological response to telaprevir with pegylated interferon and ribavirin for chronic hepatitis C. Antivir Ther 2014; 20:185-92. [DOI: 10.3851/imp2805] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/16/2014] [Indexed: 10/25/2022]
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Debing Y, Neyts J. Antiviral strategies for hepatitis E virus. Antiviral Res 2013; 102:106-18. [PMID: 24374149 PMCID: PMC7113752 DOI: 10.1016/j.antiviral.2013.12.005] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2013] [Revised: 12/12/2013] [Accepted: 12/14/2013] [Indexed: 02/08/2023]
Abstract
The hepatitis E virus is a common cause of acute hepatitis. Contrary to hepatitis B and C, hepatitis E is mostly a mild infection, although it has a high mortality in pregnant women and can evolve to chronicity in immunocompromised patients. Ribavirin and pegylated interferon-α are the only available therapies, but both have side effects that are not acceptable for prophylaxis or treatment of mild infections. In addition, these drugs cannot be used for all patient types (e.g. in case of pregnancy, specific organ transplants or co-morbidities) and in resource-poor settings. Hence there is an urgent need for better antiviral treatments that are efficacious and safe, also during pregnancy. In this review, a concise introduction to the virus and disease is provided, followed by a discussion of the available assay systems and potential molecular targets (viral proteins and host factors) for the development of inhibitors of HEV replication. Finally, directions for future research are presented.
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Affiliation(s)
- Yannick Debing
- Rega Institute for Medical Research, Department of Microbiology and Immunology, Minderbroedersstraat 10, 3000 Leuven, Belgium
| | - Johan Neyts
- Rega Institute for Medical Research, Department of Microbiology and Immunology, Minderbroedersstraat 10, 3000 Leuven, Belgium.
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Ogawa E, Furusyo N, Murata M, Ikezaki H, Ihara T, Hayashi T, Toyoda K, Okada K, Kainuma M, Kajiwara E, Takahashi K, Satoh T, Hayashi J. Valuable antiviral therapeutic options for the treatment of chronic hepatitis C patients with thrombocytopenia. J Viral Hepat 2013; 20:838-46. [PMID: 24304453 DOI: 10.1111/jvh.12109] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2012] [Accepted: 02/21/2013] [Indexed: 01/22/2023]
Abstract
Thrombocytopenia in patients with chronic hepatitis C may represent an obstacle for the initiation of antiviral treatment. The aim of this study was to evaluate factors predictive of successful pegylated interferon (PEG-IFN) α2b and ribavirin (RBV) treatment for patients with thrombocytopenia with no history of splenectomy or partial splenic embolization. One hundred and fifty-one chronic hepatitis C patients (genotype 1: n = 110, genotype 2: n = 41) with TCP (<100 × 10(9) /L) at baseline were enrolled. Pretreatment variables included interleukin 28B (IL28B) genotype (rs8099917) and homoeostasis model assessment of insulin resistance score (HOMA-IR). The kinetics of haemoglobin and platelets according to the inosine triphosphatase (ITPA) genotype (rs1127354) were investigated. Sustained virological response (SVR) was significantly more frequent in hepatitis C virus (HCV) genotype 2 (65.9%) than in genotype 1 (34.5%) patients (P < 0.0001). Multiple logistic regression analysis of HCV genotype 1 extracted IL28B TT genotype [odds ratio (OR) 5.97, P = 0.006] and HOMA-IR <2.5 (OR 7.14, P = 0.0016) as significant independent pretreatment predictors of SVR. The analyses of HCV genotype 2 showed that HOMA-IR was significantly related to SVR, but IL28B genotype was not. Patients with ITPA CC genotype showed a significant haemoglobin reduction and lower degree of platelets decrease than those with ITPA CA/AA genotypes. The most common reason for premature discontinuation of treatment was the development of hepatocellular carcinoma (n = 8, 5.3%). In conclusion, HOMA-IR is a useful predictor of SVR for patients with thrombocytopenia infected with HCV genotype 1 or 2 treated with PEG-IFNα2b and RBV. The inclusion of IL28B, ITPA genotypes and HOMA-IR adds valuable therapeutic information.
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Affiliation(s)
- E Ogawa
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan; Department of Environmental Medicine and Infectious Disease, Kyushu University, Fukuoka, Japan
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Ogawa E, Furusyo N, Nakamuta M, Kajiwara E, Nomura H, Dohmen K, Takahashi K, Satoh T, Azuma K, Kawano A, Tanabe Y, Kotoh K, Shimoda S, Hayashi J. Telaprevir-based triple therapy for chronic hepatitis C patients with advanced fibrosis: a prospective clinical study. Aliment Pharmacol Ther 2013; 38:1076-85. [PMID: 24099469 DOI: 10.1111/apt.12494] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2013] [Revised: 07/27/2013] [Accepted: 08/29/2013] [Indexed: 12/20/2022]
Abstract
BACKGROUND Antiviral treatment is recommended for chronic hepatitis C patients with advanced fibrosis to reduce and prevent cirrhosis-related complications. AIM To evaluate the efficacy and safety of telaprevir (TVR)-based triple therapy for patients with advanced fibrosis in a clinical practice setting. METHODS This prospective, multicentre study consisted of 102 patients with advanced fibrosis (METAVIR score F3-4) who were infected with HCV genotype 1b. All received 12 weeks of TVR in combination with 24 weeks of pegylated interferon (PEG-IFN) α2b and ribavirin (RBV). RESULTS The sustained virological response (SVR) rate was 69.6% (71 of 102). Notably, for treatment-naïve and prior relapse patients the SVR rate was over 80%. Previous treatment response, interleukin 28B polymorphism (rs8099917) and rapid virological response (undetectable HCV RNA at week 4) were independently associated with SVR. To achieve SVR, an adequate dosage of PEG-IFNα2b (≥1.2 μg/kg/week) and RBV (≥7.5 mg/kg/day) is preferable; however, the mean weight-adjusted TVR dosage had little impact on treatment outcome. Although severe blood cytopaenia and a dermatological disorder were frequently found, the rate of discontinuation due to adverse effects was 12.7%. The inosine triphosphatase CC allele (rs1127354) was independently associated with the development of severe anaemia, and lower serum albumin level (<35 g/L) was associated with the occurrence of infection. CONCLUSIONS The great gain in the SVR rate by telaprevir-based triple therapy offsets the problems with adverse effects; thus, it should be considered as a potent treatment protocol for patients with advanced fibrosis, especially for those with treatment-naïve and prior relapse.
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Affiliation(s)
- E Ogawa
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
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Scherzer TM, Stättermayer AF, Stauber R, Maieron A, Strasser M, Laferl H, Schwarzer R, Datz C, Rutter K, Beinhardt S, Steindl-Munda P, Hofer H, Ferenci P. Effect of gender and ITPA polymorphisms on ribavirin-induced anemia in chronic hepatitis C patients. J Hepatol 2013; 59:964-71. [PMID: 23850877 DOI: 10.1016/j.jhep.2013.06.030] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2013] [Revised: 06/25/2013] [Accepted: 06/29/2013] [Indexed: 01/15/2023]
Abstract
BACKGROUND & AIMS Single nucleotide polymorphisms (SNPs) in the inosine triphosphate pyrophosphatase (ITPA) gene protect patients from ribavirin induced anemia. To investigate other possible protective cofactors, gender differences were analyzed in patients with HCV genotype 1. METHODS Hemoglobin levels at baseline (Hb0) and the decline after 4 weeks of treatment (HbΔ4) were analyzed in 308 chronic hepatitis C patients participating in 5 Austrian trials (n=308, age 43.9 ± 11.1, male:185, female:123, BMI 25.3 ± 3.9, no cirrhosis: n=259, liver cirrhosis: n=49). All patients were treated with 180 μg peginterferon-alpha 2a and ribavirin [1000-1200 mg/d; females: mean (95% CI) 15.8 mg/kg (15.4-16.2); males 14.3 (14.1-14.5); p<0.001]. The SNPs rs6051702, rs1127354, rs7270101 and IL28B rs12979860 were analyzed by the StepOnePlus Real time PCR System. RESULTS 188 were major alleles homozygotes; 95 (30.8%) carried the minor allele (C) of rs6051702, 47 (15.3%) of rs1127354 (A), and 69 (22.4%) of rs7270101 (C). The overall Hb0 was 14.8 g/dl (14.6-14.9) [mean (95%CI); females 13.7 (13.5-13.9); males 15.5; 15.3-15.6; p<0.001]. The overall HbΔ4 was greater in major allele homozygotes [2.8 g/dl (2.6-3.0)] than in minor allele carriers [1.6 (1.4-1.9); p<0.001]. Irrespective of the ITPA genotypes HbΔ4 was smaller in female [2.0 (1.7-2.2)] than in male patients [2.6 (2.4-2.8); p<0.001] and among females in premenopausal [1.5 (1.3-1.8)] than in postmenopausal patients [2.7 (2.3-3.1); p<0.001]. CONCLUSIONS Irrespective of the protective effect of ITPA mutations, premenopausal females less likely develop ribavirin induced anemia.
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Development and evaluation of solid lipid nanoparticles of raloxifene hydrochloride for enhanced bioavailability. BIOMED RESEARCH INTERNATIONAL 2013; 2013:584549. [PMID: 24228255 PMCID: PMC3817799 DOI: 10.1155/2013/584549] [Citation(s) in RCA: 105] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/13/2013] [Revised: 07/30/2013] [Accepted: 08/13/2013] [Indexed: 01/21/2023]
Abstract
Raloxifene hydrochloride (RL-HCL) is an orally selective estrogen receptor modulator (SERM) with poor bioavailability of nearly 2% due to its poor aqueous solubility and extensive first pass metabolism. In order to improve the oral bioavailability of raloxifene, raloxifene loaded solid lipid nanoparticles (SLN) have been developed using Compritol 888 ATO as lipid carrier and Pluronic F68 as surfactant. Raloxifene loaded SLN were prepared by solvent emulsification/evaporation method, and different concentrations of surfactant, and homogenization speed were taken as process variables for optimization. SLN were characterized for particle size, zeta potential, entrapment efficiency, surface morphology, and crystallinity of lipid and drug. In vitro drug release studies were performed in phosphate buffer of pH 6.8 using dialysis bag diffusion technique. Particle sizes of all the formulations were in the range of 250 to 1406 nm, and the entrapment efficiency ranges from 55 to 66%. FTIR and DSC studies indicated no interaction between drug and lipid, and the XRD spectrum showed that RL-HCL is in amorphous form in the formulation. In vitro release profiles were biphasic in nature and followed Higuchi model of release kinetics. Pharmacokinetics of raloxifene loaded solid lipid nanoparticles after oral administration to Wistar rats was studied. Bioavailability of RL-HCL loaded SLN was nearly five times than that of pure RL-HCL.
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Furusyo N, Ogawa E, Murata M, Toyoda K, Ohnishi H, Eiraku K, Shimizu M, Harada Y, Mitsumoto F, Takayama K, Kainuma M, Okada K, Hayashi J. Therapeutic drug monitoring of telaprevir in chronic hepatitis C patients receiving telaprevir-based triple therapy is useful for predicting virological response. J Antimicrob Chemother 2013; 69:483-90. [PMID: 24092661 DOI: 10.1093/jac/dkt371] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
OBJECTIVES This prospective, pharmacokinetic study was done to investigate the impact of telaprevir plasma trough concentration (Ctrough) in the early stage of treatment on the response to telaprevir-based triple therapy for chronic hepatitis C patients. METHODS Participants were 70 chronic hepatitis C patients infected with genotype 1. All patients received 12 week triple therapy that included telaprevir (2250 mg/day), pegylated interferon-α2b (pegylated-IFNα2b) (60-150 μg/week) and ribavirin (600-1000 mg/day) followed by a 12 week dual therapy that included pegylated-IFNα2b and ribavirin. Plasma telaprevir Ctrough was determined by a validated assay using HPLC at days 3, 7 and 14. The study was registered as a clinical trial on the University Hospital Medical Information Network (ID 000009656). RESULTS The rates of undetectable hepatitis C virus RNA at week 4 [rapid virological response (RVR)] and at 24 weeks after therapy [sustained virological response (SVR)] were 71.4% and 82.9%, respectively. Of the patients with RVR, 90% achieved SVR. The mean telaprevir Ctrough levels at days 3, 7 and 14 of SVR patients (2.748, 2.733 and 2.999 μg/mL, respectively) were significantly higher than those of non-SVR patients (1.616, 1.788 and 2.314 μg/mL, respectively) (all P < 0.05). Multiple logistic regression analysis of possible predictors of SVR extracted higher telaprevir Ctrough at day 3 (OR 1.012 by 0.001 μg/mL, P < 0.0001) and interleukin 28B (rs8099917) TT allele (OR 6.16 versus non-TT alleles, P < 0.0001). CONCLUSIONS Therapeutic drug monitoring of telaprevir in the early stage of treatment is useful in clinical practice for predicting the virological response of patients receiving telaprevir-based triple therapy.
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Affiliation(s)
- Norihiro Furusyo
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
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Ogawa E, Furusyo N, Nakamuta M, Kajiwara E, Nomura H, Dohmen K, Takahashi K, Satoh T, Azuma K, Kawano A, Tanabe Y, Kotoh K, Shimoda S, Hayashi J. Clinical milestones for the prediction of severe anemia by chronic hepatitis C patients receiving telaprevir-based triple therapy. J Hepatol 2013; 59:667-74. [PMID: 23707372 DOI: 10.1016/j.jhep.2013.05.017] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2013] [Revised: 04/19/2013] [Accepted: 05/13/2013] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Anemia is a common adverse effect of telaprevir (TVR) in combination with pegylated interferon (PegIFN)α and ribavirin (RBV) therapy. It occurs at a higher incidence with the TVR relative to PegIFNα and RBV alone. We herein evaluate the baseline and on-treatment predictors of the development of severe anemia by chronic hepatitis C virus (HCV) patients receiving TVR-based triple therapy. METHODS This prospective, multicenter study consisted of 292 patients (median age: 62 years) infected with HCV genotype 1. All received 12 weeks of TVR in combination with 24 weeks of PegIFNα2b and RBV. The definition of severe anemia during antiviral treatment is hemoglobin (Hb)<85 g/L. RESULTS 101 (34.6%) patients developed severe anemia during the treatment period. Multivariable logistic regression analysis of possible pretreatment predictors of the development of severe anemia extracted baseline Hb < 135 g/L (Hazard ratio [HR], 2.53; p = 0.0013), estimated glomerular filtration rate <80 ml/min/1.73 m(2) (HR, 1.83; p = 0.0265), and inosine triphosphatase (ITPA) CC genotype (rs1127354) (HR, 2.91; p = 0.0024). For patients with ITPA CC (n = 227), multivariable logistic regression analysis of possible pretreatment and on-treatment predictors of the development of severe anemia extracted Hb level at week 2 (HR, 0.96; p = 0.0085) and the initial four weeks of weight-adjusted TVR (HR, 1.05; p = 0.0281). CONCLUSIONS Anemia remains a risk for all patients treated with TVR-based triple therapy. However, ITPA polymorphism (rs1127354) is useful for predicting the development of severe anemia and will be helpful in the management of treatment.
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Affiliation(s)
- Eiichi Ogawa
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
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Ogawa E, Furusyo N, Murata M, Toyoda K, Eiraku K, Shimizu M, Harada Y, Mitsumoto F, Takayama K, Okada K, Kainuma M, Hayashi J. Early phase viral kinetics of chronic hepatitis C patients receiving telaprevir-based triple therapy: A comparison of two real-time PCR assays. Antiviral Res 2013; 99:119-24. [DOI: 10.1016/j.antiviral.2013.05.002] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2013] [Revised: 05/03/2013] [Accepted: 05/06/2013] [Indexed: 12/12/2022]
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Telaprevir can be successfully and safely used to treat older patients with genotype 1b chronic hepatitis C. J Hepatol 2013; 59:205-12. [PMID: 23542346 DOI: 10.1016/j.jhep.2013.03.020] [Citation(s) in RCA: 63] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2013] [Revised: 03/12/2013] [Accepted: 03/13/2013] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS This study was performed to evaluate the efficacy of a triple therapy in older Japanese patients; telaprevir (TVR) was added to pegylated interferon α2b and ribavirin. METHODS This prospective study enrolled 120 genotype 1b patients with chronic hepatitis C who received 12 weeks of triple therapy followed by a 12-week dual therapy that included pegylated interferon α2b and ribavirin. Patients were categorized according to age: group A, 64 patients aged >60 and group B, 56 patients aged ⩽60. Serum HCV RNA levels were monitored by COBAS TaqMan HCV test. RESULTS The rates of undetectable HCV RNA at week 4 (rapid virological response, RVR) were 73.4% in group A and 73.2% in group B. No significant difference in sustained virological response (SVR) was found between groups A (76.6%) and B (83.9%) (p=0.314). The SVR rates for patients with interleukin 28B (IL28B) (rs8099917) TT allele (89.4% and 91.9% for groups A and B) were significantly higher than for those with the IL28B TG/GG allele (41.2% and 68.4%, respectively) (both p<0.05). Multivariate analysis extracted IL28B TT and RVR as independent factors associated with SVR. Adverse effects resulted in treatment discontinuation by 12.5% in each group. Hemoglobin decrease significantly differed between groups A and B: the decrease to ≤100 g/L, to 85 - <100g/L, and to <85 g/L, was 9.4%, 40.6%, and 50% in group A patients, respectively, and 41.1%, 25%, and 33.9% in group B patients, respectively (p=0.0006). CONCLUSIONS TVR-based triple therapy can be successfully used to treat older patients with genotype 1b chronic hepatitis C.
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Raloxifene hydrochloride as hepatitis C treatment. Ann Hepatol 2013. [DOI: 10.1016/s1665-2681(19)31402-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 08/29/2023]
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