Summary of antifungal agents used in Fungal Keratitis.
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More than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\\n\\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\\n\\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\\n\\nAdditionally, each book published by IntechOpen contains original content and research findings.
\\n\\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\\n\\n\\n\\n
\\n"}]',published:!0,mainMedia:{caption:"IntechOpen Maintains",originalUrl:"/media/original/113"}},components:[{type:"htmlEditorComponent",content:'
Simba Information has released its Open Access Book Publishing 2020 - 2024 report and has again identified IntechOpen as the world’s largest Open Access book publisher by title count.
\n\nSimba Information is a leading provider for market intelligence and forecasts in the media and publishing industry. The report, published every year, provides an overview and financial outlook for the global professional e-book publishing market.
\n\nIntechOpen, De Gruyter, and Frontiers are the largest OA book publishers by title count, with IntechOpen coming in at first place with 5,101 OA books published, a good 1,782 titles ahead of the nearest competitor.
\n\nSince the first Open Access Book Publishing report published in 2016, IntechOpen has held the top stop each year.
\n\n\n\nMore than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\n\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\n\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\n\nAdditionally, each book published by IntechOpen contains original content and research findings.
\n\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\n\n\n\n
\n'}],latestNews:[{slug:"intechopen-supports-asapbio-s-new-initiative-publish-your-reviews-20220729",title:"IntechOpen Supports ASAPbio’s New Initiative Publish Your Reviews"},{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"}]},book:{item:{type:"book",id:"9993",leadTitle:null,fullTitle:"Earthquakes - From Tectonics to Buildings",title:"Earthquakes",subtitle:"From Tectonics to Buildings",reviewType:"peer-reviewed",abstract:"Earthquakes - From Tectonics to Buildings is a compilation of eight chapters that explain tectonics and seismicity. The book presents state-of-the-art techniques for calculating ground motion amplification due to sediments above the engineering bedrock employing strong-motion recordings and microtremor data. It also explains liquefaction phenomena through interpretive structural modeling techniques. Finally, the book presents pile foundations’ seismic behavior on liquefiable soils and remedial countermeasures against earthquake attacks.",isbn:"978-1-83962-429-2",printIsbn:"978-1-83962-424-7",pdfIsbn:"978-1-83962-430-8",doi:"10.5772/intechopen.87816",price:119,priceEur:129,priceUsd:155,slug:"earthquakes-from-tectonics-to-buildings",numberOfPages:224,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"1f9859a0a16af53d80bf3952fba7a272",bookSignature:"Walter Salazar",publishedDate:"May 19th 2021",coverURL:"https://cdn.intechopen.com/books/images_new/9993.jpg",numberOfDownloads:3112,numberOfWosCitations:1,numberOfCrossrefCitations:7,numberOfCrossrefCitationsByBook:0,numberOfDimensionsCitations:9,numberOfDimensionsCitationsByBook:0,hasAltmetrics:0,numberOfTotalCitations:17,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"June 9th 2020",dateEndSecondStepPublish:"September 10th 2020",dateEndThirdStepPublish:"November 9th 2020",dateEndFourthStepPublish:"January 28th 2021",dateEndFifthStepPublish:"March 29th 2021",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6,7",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"236461",title:"Dr.",name:"Walter",middleName:null,surname:"Salazar",slug:"walter-salazar",fullName:"Walter Salazar",profilePictureURL:"https://mts.intechopen.com/storage/users/236461/images/system/236461.jpg",biography:"Dr. Walter Salazar is a structural civil engineer who obtained a doctoral degree in Engineering Seismology from the Interdisciplinary Graduate School of Science and Engineering, Tokyo Institute of Technology, Japan, in 2004. Dr. Salazar has been active in site-effects and seismic hazard research, producing several peer-reviewed maps for El Salvador, Jamaica, and the Eastern Caribbean. He has published sixty articles in peer-reviewed journals, books, and international conferences. In 2011, he received a Distinguished Salvadoran National Award. He is a peer reviewer for several scientific journals. Currently, Dr. Salazar is a Professor of Structural Engineering at the Catholic University of El Salvador.",institutionString:"Catholic University of El Salvador",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"2",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"Catholic University of El Salvador",institutionURL:null,country:{name:"El Salvador"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"654",title:"Seismology",slug:"seismology"}],chapters:[{id:"74492",title:"Tentative Intracontinental Seismic Activity in South Siberia and Russian Far East",doi:"10.5772/intechopen.95073",slug:"tentative-intracontinental-seismic-activity-in-south-siberia-and-russian-far-east",totalDownloads:315,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Overwhelming majority of minor, strong and major earthquakes in south Siberia and Russian Far East coincide with relatively narrow intracontinental zones on the boundaries of blocks and lithosphere plates. The geodynamic activity of these zones connects, besides the plate interaction, with deep lithosphere structure and anomalies of the different geophysical fields as well as with blocks’ kinematics. Authors’ located areas of the seismic centers origin and the possible manifestations of the high seismicity based on the distribution of the maximal volumes of releasing seismic energy. We established these areas, with certain care, in the northeast Altai and adjacent part of the west Sayany, in the west of the east Sayany, around the Baikal Lake and in northwest Transbaikalia, in the east of Transbaikalia between the Vitim River and upper stream of the Aldan River, and in the north of the Sakhalin Island. The majority of minor and strong, rarely major, earthquakes took place in these areas. Deep and near surface structural peculiarities influence on these areas’ geodynamics and allow establishing possible levels of seismic energy releasing. We draw areas of intensive seismic energy releasing with its calculating for each from investigated regions. They gravitate towards interblock zones, which separate crust blocks and the North Eurasian Lithosphere Plate. The fulfilled investigation allows establishing specific areas of the increased seismicity in south Siberia, Russian Far East and adjacent territories.",signatures:"Yuriy Gatinsky and Tatiana Prokhorova",downloadPdfUrl:"/chapter/pdf-download/74492",previewPdfUrl:"/chapter/pdf-preview/74492",authors:[{id:"325581",title:"Dr.",name:"Yuriy",surname:"Gatinsky",slug:"yuriy-gatinsky",fullName:"Yuriy Gatinsky"},{id:"325590",title:"Dr.",name:"Tatiana",surname:"Prokhorova",slug:"tatiana-prokhorova",fullName:"Tatiana Prokhorova"}],corrections:null},{id:"74480",title:"Tectonics and Seismicity in the periAdriatic Zones: Implications for Seismic Hazard in Italy",doi:"10.5772/intechopen.94924",slug:"tectonics-and-seismicity-in-the-periadriatic-zones-implications-for-seismic-hazard-in-italy",totalDownloads:400,totalCrossrefCites:2,totalDimensionsCites:4,hasAltmetrics:0,abstract:"The recognition of the seismic zones most prone to next major earthquakes in Italy would considerably help the choice of the most efficient prevention plan. This work describes an attempt to gain reliable information about that problem by exploiting the knowledge about the short-term development of the ongoing tectonic processes in the study area and its influence on the spatio-temporal distribution of major shocks. In the periAdriatic zones, such distribution is connected with the progressive northward displacement of the Adria plate, that is controlled by the progressive activation of the decoupling fault systems in the surrounding belts (Dinarides, Apennines and Eastern Southern Alps). The reliability of this hypothesis is evaluated by analysing the seismic histories of the periAdriatic zones. The regularity patterns that are tentatively recognised in such histories are used to identify the most probable location of next major shocks. Further insights into the present seismic hazard in the Southern Apennines and Calabria are tentatively inferred from tectonic connections between these regions and other periAdriatic zones, suggested by the seismic histories in the last 2–4 centuries and the geodynamic/tectonic context in the central Mediterranean area.",signatures:"Enzo Mantovani, Caterina Tamburelli, Daniele Babbucci, Marcello Viti and Nicola Cenni",downloadPdfUrl:"/chapter/pdf-download/74480",previewPdfUrl:"/chapter/pdf-preview/74480",authors:[{id:"326290",title:"Prof.",name:"Enzo",surname:"Mantovani",slug:"enzo-mantovani",fullName:"Enzo Mantovani"},{id:"336991",title:"Dr.",name:"Caterina",surname:"Tamburelli",slug:"caterina-tamburelli",fullName:"Caterina Tamburelli"},{id:"336993",title:"Dr.",name:"Daniele",surname:"Babbucci",slug:"daniele-babbucci",fullName:"Daniele Babbucci"},{id:"336994",title:"Dr.",name:"Marcello",surname:"Viti",slug:"marcello-viti",fullName:"Marcello Viti"},{id:"336996",title:"Dr.",name:"Nicola",surname:"Cenni",slug:"nicola-cenni",fullName:"Nicola Cenni"}],corrections:null},{id:"74466",title:"Seismological Data Acquisition and Analysis within the Scope of Citizen Science",doi:"10.5772/intechopen.95273",slug:"seismological-data-acquisition-and-analysis-within-the-scope-of-citizen-science",totalDownloads:548,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:0,abstract:"From 2017 till 2020 a low cost seismic sensor network was built in the southern Vienna Basin, Lower Austria, as a part of ongoing educational and citizen science projects. The purpose of the project is to inform society about the seismic activity in this area and to include authorities and interested citizens into data acquisition and exploitation. Near real time (NRT) seismic data are made accessible online. Seismic events are detected and archived automatically. The visualization of these events online facilitates instantaneously estimates of the extent of the shaking area and potential damage. Peak ground velocities (PGV) are related to macroseismic intensities (EMS-98) derived from reports about ground motion felt in the vicinity of the network stations. Observed amplitudes and travel times are modeled by simple, but effective relations. Traditional and innovative localization methods based on travel times and amplitudes are applied and analyzed with respect to data quality and localization accuracy. All results are accessible online and the computer code is open and applicable, e.g. for educational purposes.",signatures:"Ewald Brückl, Peter Carniel, Stefan Mertl and Rita Meurers",downloadPdfUrl:"/chapter/pdf-download/74466",previewPdfUrl:"/chapter/pdf-preview/74466",authors:[{id:"324000",title:"Emeritus Prof.",name:"Ewald",surname:"Brückl",slug:"ewald-bruckl",fullName:"Ewald Brückl"},{id:"339983",title:"Mr.",name:"Peter",surname:"Carniel",slug:"peter-carniel",fullName:"Peter Carniel"},{id:"339987",title:"Dr.",name:"Stefan",surname:"Mertl",slug:"stefan-mertl",fullName:"Stefan Mertl"},{id:"339993",title:"MSc.",name:"Rita",surname:"Meurers",slug:"rita-meurers",fullName:"Rita Meurers"}],corrections:null},{id:"75465",title:"Seismicity at Newdigate, Surrey, during 2018–2019: A Candidate Mechanism Indicating Causation by Nearby Oil Production",doi:"10.5772/intechopen.94923",slug:"seismicity-at-newdigate-surrey-during-2018-2019-a-candidate-mechanism-indicating-causation-by-nearby",totalDownloads:329,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:0,abstract:"During 2018–2019, oil was intermittently produced from the Late Jurassic Upper Portland Sandstone in the Weald Basin, southeast England, via the Horse Hill-1 and Brockham-X2Y wells. Concurrently, a sequence of earthquakes of magnitude ≤3.25 occurred near Newdigate, ∼3 km and ∼8 km from these wells. The pattern, with earthquakes concentrated during production from this Portland reservoir, suggests a cause-and-effect connection. It is proposed that this seismicity occurred on a patch of fault transecting permeable Dinantian limestone, beneath the Jurassic succession of the Weald Basin, hydraulically connected to this reservoir via this permeable fault and the permeable calcite ‘beef’ fabric within the Portland sandstone; oil production depressurizes this reservoir and draws groundwater from the limestone, compacting it and ‘unclamping’ the fault, reaching the Mohr-Coulomb failure criterion and causing seismicity. In principle this model is fully testable, but required data, notably the history of pressure variations in the wells, are not currently in the public domain. Quantitative estimates are, nonetheless, made of the magnitudes of the variations, arising from production from each well, in the state of stress on the seismogenic Newdigate fault. The general principles of this model, including the incorporation of poroelastic effects and effects of fault asperities into Mohr-Coulomb failure calculations, may inform understanding of anthropogenic seismicity in other settings.",signatures:"Rob Westaway",downloadPdfUrl:"/chapter/pdf-download/75465",previewPdfUrl:"/chapter/pdf-preview/75465",authors:[{id:"330592",title:"Dr.",name:"Rob",surname:"Westaway",slug:"rob-westaway",fullName:"Rob Westaway"}],corrections:null},{id:"74862",title:"S-Wave Site Amplification Factors from Observed Ground Motions in Japan: Validation of Delineated Velocity Structures and Proposal for Empirical Correction",doi:"10.5772/intechopen.95478",slug:"s-wave-site-amplification-factors-from-observed-ground-motions-in-japan-validation-of-delineated-vel",totalDownloads:330,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:0,abstract:"We first derived site amplification factors (SAFs) from the observed strong motions by the Japanese nationwide networks, namely, K-NET and KiK-net of National Institute of Earthquake Research and Disaster Resilience and Shindokei (Instrumental Seismic Intensity) Network of Japan Meteorological Agency by using the so-called generalized spectral inversion technique. We can use these SAFs for strong motion prediction at these observation sites, however, we need at least observed weak motion or microtremor data to quantify SAF at an arbitrary site. So we tested the capability of the current velocity models in Japan whether they can reproduce or not the observed SAFs at the nearest grid of every 250 m as the one-dimensional theoretical transfer functions (TTF). We found that at about one-half of the sites the calculated 1D TTFs show more or less acceptable fit to the observed SAFs, however, the TTFs tend to underestimate the observed SAFs in general. Therefore, we propose a simple, empirical method to fill the gap between the observed SAFs and the calculated TTFs. Validation examples show that our proposed method effectively predict better SAFs than the direct substitute of TTFs at sites without observed data.",signatures:"Eri Ito, Kenichi Nakano, Shigeki Senna and Hiroshi Kawase",downloadPdfUrl:"/chapter/pdf-download/74862",previewPdfUrl:"/chapter/pdf-preview/74862",authors:[{id:"330550",title:"Prof.",name:"Hiroshi",surname:"Kawase",slug:"hiroshi-kawase",fullName:"Hiroshi Kawase"},{id:"330553",title:"MSc.",name:"Eri",surname:"Ito",slug:"eri-ito",fullName:"Eri Ito"},{id:"330554",title:"Dr.",name:"Kenichi",surname:"Nakano",slug:"kenichi-nakano",fullName:"Kenichi Nakano"},{id:"342138",title:"Dr.",name:"Shigeki",surname:"Senna",slug:"shigeki-senna",fullName:"Shigeki Senna"}],corrections:null},{id:"74560",title:"Assessing Seismic Site Response at Areas Characterized by a Thick Buried Low-Velocity Layer",doi:"10.5772/intechopen.95277",slug:"assessing-seismic-site-response-at-areas-characterized-by-a-thick-buried-low-velocity-layer",totalDownloads:276,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Earthquake ground motion is dependent on various factors, including local ground conditions. Whilst many studies have characterized the effect of having outcropping “soft” geological layers which have the ability to amplify ground motion, there is minimal literature on the effect of having such layers embedded between two harder layers. This situation creates a seismic wave velocity inversion. The Maltese islands (Central Mediterranean) present a good opportunity for the study of velocity inversion as almost half of the islands are characterized by a thick buried layer of clay. The results presented in this chapter are a combination of studies which have been conducted on the Maltese islands, using non-invasive geophysical prospecting techniques in areas characterized by a thick buried low-velocity layer, to characterize the response of earthquake ground shaking in such geological situations.",signatures:"Daniela Farrugia, Pauline Galea and Sebastiano D’Amico",downloadPdfUrl:"/chapter/pdf-download/74560",previewPdfUrl:"/chapter/pdf-preview/74560",authors:[{id:"58678",title:"Dr.",name:"Pauline",surname:"Galea",slug:"pauline-galea",fullName:"Pauline Galea"},{id:"330447",title:"Dr.",name:"Daniela",surname:"Farrugia",slug:"daniela-farrugia",fullName:"Daniela Farrugia"},{id:"339851",title:"Dr.",name:"Sebastiano",surname:"D'Amico",slug:"sebastiano-d'amico",fullName:"Sebastiano D'Amico"}],corrections:null},{id:"76179",title:"Elucidation of Seismic Soil Liquefaction Significant Factors",doi:"10.5772/intechopen.97278",slug:"elucidation-of-seismic-soil-liquefaction-significant-factors",totalDownloads:258,totalCrossrefCites:2,totalDimensionsCites:2,hasAltmetrics:0,abstract:"The paper develops a framework to analyze the interactions among seismic soil liquefaction significant factors using the interpretive structural model (ISM) approach based on cone penetration test. To identify the contextual relationships among the significant factors, systematic literature review approach was used bearing in mind the selection principle. Since multiple factors influence seismic soil liquefaction, determining all factors in soil liquefaction would be extremely difficult, as even a few seismic soil liquefaction factors are not easy to deal with. This study highlighted two main characteristics of seismic soil liquefaction factors. First, the seismic soil liquefaction factors–peak ground acceleration F2 (amax), equivalent clean sand penetration resistance F5 (qc1Ncs), and thickness of soil layer F11 (Ts) influenced soil liquefaction directly and were located at level 2 (top level) in the ISM model, meaning they require additional seismic soil liquefaction factors except thickness of soil layer F11 (Ts) to collaboratively impact on soil liquefaction potential. The multilevel hierarchy reveals that depth of soil deposit F10 (Ds) is formed the base of ISM hierarchy. Secondly, Matrice d’impacts croisés multiplication appliqués à un classement (MICMAC) analysis has been employed for evaluating these identified factors in accordance with driving power and dependence power. Factors with a higher driving power should be given special consideration. Autonomous soil liquefaction factors have no reliance on other soil liquefaction factors and interfere less. In order to identify the significant factors that affect seismic soil liquefaction susceptibility, the model built in this study clearly illustrates the complex relationships between factors and demonstrates the direct and indirect relationships.",signatures:"Mahmood Ahmad, Xiaowei Tang, Feezan Ahmad, Marijana Hadzima-Nyarko, Ahsan Nawaz and Asim Farooq",downloadPdfUrl:"/chapter/pdf-download/76179",previewPdfUrl:"/chapter/pdf-preview/76179",authors:[{id:"298331",title:"Dr.",name:"Mahmood",surname:"Ahmad",slug:"mahmood-ahmad",fullName:"Mahmood Ahmad"},{id:"329439",title:"Prof.",name:"Xiaowei",surname:"Tang",slug:"xiaowei-tang",fullName:"Xiaowei Tang"}],corrections:null},{id:"74449",title:"The Dynamic Behaviour of Pile Foundations in Seismically Liquefiable Soils: Failure Mechanisms, Analysis, Re-Qualification",doi:"10.5772/intechopen.94936",slug:"the-dynamic-behaviour-of-pile-foundations-in-seismically-liquefiable-soils-failure-mechanisms-analys",totalDownloads:657,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"This chapter presents a concise overview of the mechanics of failure, analysis and requalification procedures of pile foundations in liquefiable soils during earthquakes. The aim is to build a strong conceptual and technical interpretation in order to gain insight into the mechanisms governing the failure of structures in liquefaction and specify effective requalification techniques. In this regard, several most common failure mechanisms of piles during seismic liquefaction such as bending (flexural), buckling instability and dynamic failure of the pile are introduced. Furthermore, the dynamic response commentary is provided by critically reviewing experimental investigations carried out using a shaking table and centrifuge modelling procedures. The emphasis is placed on delineating the concept of seismic design loads and important aspects of the dynamic behaviour of piles in liquefiable soils. In this context, using Winkler foundation approach with the proposed p–y curves and finite-element analyses in conjunction with numerical analysis methods, are outlined. Moreover, the feasibility of successful remediation techniques for earthquake resistance is briefly reviewed in light of the pile behaviour and failure. Finally, practical recommendations for achieving enhanced resistance of the seismic response of pile foundation in liquefiable soil are provided.",signatures:"Rohollah Rostami, Slobodan B. Mickovski, Nicholas Hytiris and Subhamoy Bhattacharya",downloadPdfUrl:"/chapter/pdf-download/74449",previewPdfUrl:"/chapter/pdf-preview/74449",authors:[{id:"225058",title:"Dr.",name:"Slobodan B.",surname:"Mickovski",slug:"slobodan-b.-mickovski",fullName:"Slobodan B. Mickovski"},{id:"324691",title:"Ph.D. Student",name:"Rohollah",surname:"Rostami",slug:"rohollah-rostami",fullName:"Rohollah Rostami"},{id:"324955",title:"Prof.",name:"Subhamoy",surname:"Bhattacharya",slug:"subhamoy-bhattacharya",fullName:"Subhamoy Bhattacharya"},{id:"324956",title:"Prof.",name:"Nicholas",surname:"Hytiris",slug:"nicholas-hytiris",fullName:"Nicholas Hytiris"}],corrections:null}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},subseries:null,tags:null},relatedBooks:[{type:"book",id:"2227",title:"Tectonics",subtitle:"Recent Advances",isOpenForSubmission:!1,hash:"3b4c2f80af61284334fb3655852de9f7",slug:"tectonics-recent-advances",bookSignature:"Evgenii Sharkov",coverURL:"https://cdn.intechopen.com/books/images_new/2227.jpg",editedByType:"Edited by",editors:[{id:"32743",title:"Prof.",name:"Evgenii",surname:"Sharkov",slug:"evgenii-sharkov",fullName:"Evgenii Sharkov"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"2051",title:"Earthquake Research and Analysis",subtitle:"Statistical Studies, Observations and Planning",isOpenForSubmission:!1,hash:"492268d0be01c6d76f0e2e4ac5c35730",slug:"earthquake-research-and-analysis-statistical-studies-observations-and-planning",bookSignature:"Sebastiano D'Amico",coverURL:"https://cdn.intechopen.com/books/images_new/2051.jpg",editedByType:"Edited by",editors:[{id:"52181",title:"Dr.",name:"Sebastiano",surname:"D'Amico",slug:"sebastiano-d'amico",fullName:"Sebastiano D'Amico"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"892",title:"Seismic Waves",subtitle:"Research and 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He is the recipient of the prestigious Quick Hire Fellowship and Senior Research Fellowship from CSIR. He is a member of OSA (Optical Society of America), and IAENG (International Association of Engineers) organizations. He is also an author and reviewer for many journals, working as a Postdoctoral Fellow at The Innovative Technologies Laboratory, Saudi Arabia.",coeditorOneBiosketch:"Dr. Kumar received his Ph.D. from Delhi Technological University where he was awarded commendable research excellent awards. He is currently an Assistant Professor in the Electronics and Communication Engineering Department at Jaypee Institute of Information Technology, a Junior Research Fellow at Delhi Technological University, and a visiting faculty in the Department of Electronics and Communication at the Netaji Subhas University of Technology. 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It is most commonly associated with bacterial, fungal or viral microorganisms that invade into the corneal stroma, resulting in inflammation and destruction of these structures; ultimately leading to visual impairment and blindness. Fungal keratitis (FK) or keratomycosis is one of the most challenging to diagnose and difficult to treat. The prevalence of fungal keratitis is variable depending upon the geographic location. It is more common in tropical and subtropical areas and relatively rare in temperate countries. It is reported about 1–60% of all cases of microbial keratitis in various studies [1, 2, 3]. A recent review including 37 countries reported highest proportion in Vietnam (59.58%) followed by Paraguay (58%) [2, 3, 4]. The fungi that commonly cause infection of the cornea include Fusarium, Aspergillus, Curvularia, Bipolaris, and Candida [1, 2, 5].
Most of the currently available antifungal medications have limitations, such as poor bioavailability and limited ocular penetration, especially in cases with deep keratitis [6, 7, 8]. This results in slow resolution of fungal infections. In addition, fungi can penetrate deeper into corneal stroma and Descemet membrane, therefore more difficult to eradicate. Surgical excision of the infected cornea is required to control the infection in nonresponsive cases [9, 10, 11, 12]. In recent years, considerable research is being continue in the field of management of fungal keratitis and several newer antifungal agents and drug delivery techniques are being evolved to overcome these limitations and improve outcome. In this chapter, we discuss the recent advances in diagnosis and treatment of fungal keratitis with a brief discussion on pathogenesis and future considerations.
Pathogenesis of FK has not been fully elucidated. Recent studies and advances have contributed in better understanding of the complicated process and host immune response.
The common risk factors for fungal keratitis are trauma with vegetative matter or objects contaminated with soil, contact lenses, ocular surface disease, lacrimal duct occlusion, fungal skin infections, long-term use of antibiotics or steroids locally or systemically [2, 13, 14, 15, 16, 17]. Other relatively rare risk factors include history of eye surgery, herpes simplex virus keratitis, eyelid abnormalities, etc. [18, 19].
Still in developing countries, the most common risk factor for fungal keratitis is ocular trauma but in developed countries, contact lens emerged as more common risk factor. This change has been occurred due to industrialization of farming and increase use of contact lens in developed world. In a large case series of 695 cases with fungal keratitis reported from 10 tertiary eye care centres across the United States over a 7-year period, 283 (40.71%) cases involved the use of contact lens [1]. Similarly Keay et al. in a multicentre case series of 733 cases from 11 tertiary care centres across the United States reported that 37% cases were associated with refractive contact lens wear, 25% were associated with ocular trauma, and 29% were associated with ocular surface disease [20].
In a study, the storage of the anti-microbial agent alexidine in its plastic containers at higher than room temperatures was found as the reason for decreased effectiveness [21]. This temperature difference in the plastic containers led to decreased concentration of the agent in solution (2.8 times less) and a corresponding higher concentration in the walls of its plastic containers (3.1 times higher) [22]. The lens type and its soaking time significantly influences the fungicidal activity of cleaning and storage solutions and poor compliance significantly increase the risk of contamination [23, 24].
A review article found about 144 species of fungi from 92 genera as causative agents in keratitis, showing largest diversity; whereas 77 species from 42 genera of bacteria, 12 species from 4 genera of protozoa and only 4 types of viruses were implicated in infectious keratitis. However, in the majority of cases of FK the causative organism belong to a few genera: Fusarium, Aspergillus, and Candida [25]. Other fungi implicated in mycotic keratitis are Curvularia, Alternaria, and Penicillium [2, 13, 14]. The rarely reported fungal pathogens include Lasiodiplodia theobromae, Cylindrocarpon species, Metarhizium anisopliae, Paecilomyces species, and Pythium insidiosum [15, 26, 27, 28, 29].
Fungal infections initiates with adhesion of fungal cells with epithelial surfaces. Fungi produce various surface proteins to contribute to the adhesion to the corneal epithelium, which has potential fungal binding sites such as laminins, fibronectins, and collagens [30, 31]. Alterations of the corneal surface due to trauma or other predisposing condition result in easy invasion of organisms deeper into underlying layers, which leads to an innate and adaptive immune-mediated inflammation, resulting in subsequent tissue necrosis of the surrounding area, consequently leads to further tissue damage, scarring, and opacification of the cornea.
The contact between fungi and host, result in expression of pattern recognition receptors (PRRs) on host epithelial and immune cells, which recognize the fungi. PPRs are Toll-like receptors (TLRs, including TLR2 and TLR4), C-type Lectin receptors (CLRs, including Dectin-1, Dectin-2 and Mincle). Dectin-1 recognizes β-glucan in fungal cell wall, while Dectin-2 and Mincle recognize mannan of cell wall [32].
Leal et al. found that neutrophils produced NADPH oxidase to control the growth of fungi. The antifungal activity of neutrophils depended on CD18, and inhibiting thioredoxin, an antioxidant increased the sensitivity of fungal hyphae to neutrophil-mediated killing in vitro [41]. The expression of PPRs, promote the production of pro-inflammatory cytokines, as well as the recruitment of neutrophils that can also cause serious inflammatory damages to cornea leading to opacification [32, 40, 42]. In fungal keratitis, the levels of pro-inflammatory IL-1β, IL-6, IL-8, IL-17, IL-23 and IFN-γ in aqueous humor were significantly higher in comparison to the non-keratitis control group [38]. A study among a Han Chinese population of patients with FK compared controls found a particular TLR4 allele that was associated with an increased risk of developing FK [43].
Fungi can produce enzymes that degrade physical barriers and facilitate tissue invasion. The mycotoxins produced from Fusarium species can inhibit immunity, break down tissues, and promote the fungal survival in host. Corneal epithelial cells can be destroyed by some cytosolic proteins and peptide toxins produced by fungi [44]. The protease and phospholipase activities detected in
Autophagy is a lysosome-mediated degradation process, which regulates intracellular homeostasis of eukaryotes by mediating the degradation of proteins and organelles [47]. It can be activated in response to starvation, stress, hypoxia, tumor, and infection [48]. Autophagy is proved to be involved in immune responses, a previous study found that autophagy maintains the cellular and immune homeostasis during the
A study by Li C et al. reported that the progression of FK caused by
Biofilm formation is one of the primary mechanisms through which fungi evade the immune response and establish infection. Clinical isolates of Fusarium, Candida and Aspergillus have been shown to form biofilms. A study reported that
Fungal keratitis can be diagnosed based on characteristic clinical features. Patients with keratitis usually present with sudden onset of pain, photophobia, watering and discharge and reduced vision. In fungal keratitis, symptoms are much milder than the signs [53].
A fungal keratitis classically presents as a dry, raised lesion with crenate or feathery borders, presence of satellite lesions and a hypopyon. An immune ring of Wesseley may be visible due to deposition of immune complexes and inflammatory cells around the ulcer (Figures 1–5). However, a study reported that Clinicians could correctly distinguished the microbial kingdom for 54 (73%) of 74 culture-positive infections, including 41 (79%) of 52 bacterial keratitis, 5 (38%) of 13 fungal keratitis, and 8 (89%) of 9 amoebic keratitis correctly [54]. In a photographic survey, clinician were able to distinguish between bacterial and fungal aetiologies 66% of the time. In 39 cases of fungal keratitis, the clinicians predicted genus in 27% of cases and species in 7.9% of cases [55].
Plaque-like ulcer with slightly defined margins, marked conjunctival injection and chemosis; fungal isolate- candida albicans.
A dry looking lesion with greyish white raised exudate appearing as plaque with hypopyon in a 56-year-old male with fugal keratitis from Aspergillus.
A greyish white infiltrate with feathery borders and a satellite lesion in a case fungal keratitis caused by Fusarium.
Severe fungal keratitis with feathery edges in case Fusarium Keratitis.
Corneal thinning and necrosis in severe fungal keratitis caused by Fusarium in a 48-year-old male with history of topical steroid instillation.
In vivo confocal microscopy (IVCM) of the cornea has been emerged as clinically useful non-invasive technique for early diagnosis of FK. It produces images from the cornea with a resolution of one micrometer (μm), which is enough for imaging of microorganisms larger than one μm, such as Acanthamoeba cysts and fungal hyphae [56]. This provides rapid and reliable diagnosis however, a clinical consensus in the interpretation of IVCM images is still lacking.
IVCM can directly visualize filamentous fungi within the whole cornea of patients. Confocal microscopy in vivo uses serial images to create optical sections through the full-thickness of the living cornea. It allows rapid identification of fungi and can be used to differentiate between fungal species.
Brasnu et al. diagnosed all the cases of suspected fungal keratitis (five out of five) caused by different fungal species using IVCM with sensitivity equal to the direct microscopy and culture [56]. They analyzed IVCM images of keratitis obtained using the Heidelberg Retina Tomograph (HRT) II confocal microscope (Heidelberg Engineering, Heidelberg, Germany) in five patients (four patients with
The hyper-reflective elements seen on IVCM must be differentiated from the basal corneal epithelial nerves, which have a more regular branching pattern. Stromal nerves, on the other hand, are much larger in diameter (25–50 μm). There are now several studies reported the use of IVCM in diagnosis and monitoring of treatment of fungal keratitis with reported sensitivity of 80–94% [57, 58, 59, 60].
IVCM is a noninvasive in vivo technique useful for early identification of fungal elements, monitoring and guidance of treatment, and determination of the depth of infection. The limitation of IVCM are that technique is extremely user-dependent, need a skilled operator and experienced viewer. The dense corneal infiltrates or scarring could preclude proper tissue penetration and visualization.
Conventional methods for the diagnosis of fungal keratitis include staining of tissue scrapings with Gram-stain, 10% potassium hydroxide (KOH) wet mount, lactophenol cotton blue, Giemsa, or calcofluor white. Reported sensitivity of Gram staining is in the range of 36–50% [61]. KOH is a rapid and an inexpensive and one of the most commonly performed procedures for detection of fungi with a sensitivity of 61–94% and specificity of 91–97% for detecting fungus (Figure 6). Lactophenol cotton blue mounts had reported sensitivity of 85% and specificity of 90–91% [62]. Sabouraud dextrose agar medium is considered as a culture medium of choice for isolating fungi however it cause delay in diagnosis. Initial growth occurs within 72 hours in 83% of cultures and within 1 week in 97% of cultures [63]. Sometimes it may be necessary to wait for two weeks to confirm no growth in culture. Over the last decade, a number of newer methods have been devised for detection of fungi.
Fungal hyphae in KOH wet mount counterstained with methylene blue.
Polymerase chain reaction (PCR) involves repeated cycles of denaturation, amplification, and replication, in which segments of deoxyribonucleic acid (DNA) are continuously multiplied. Specific DNA primers are employed to indicate the presence of the microorganism in question [64]. PCR has emerged as a sensitive and specific test for the diagnosis of fungal keratitis. Several techniques of PCR have been evolved and currently used for identification of fungi.
Traditional PCR by using single pair of primer to amplify the target genomic sequence is simple and efficient technique, but generation of nonspecific products can affect the results. In Nested PCR, two pairs of primers are used; one set of primer is an amplified sequence, and the other is complementary to the sequence amplified by the first one. It is more specific than traditional PCR; amplifies only the specific sequences looked for; but identify a set of fungal pathogens, not a single specific species.
In multiplex PCR Multiple primer, pairs are used. Advantage is Rapid amplification of multiple sequences, conserves template DNA, and minimizes expense; recognizes many pathogens at once. In real time PCR, one set of primers is used; amplified sequence is linked with a fluorescent probe, which emits light when bound to the amplified product. It is more specific, sensitive, and reproducible but not ideal for multiplexing [65, 66, 67].
PCR reported higher sensitivity in comparison to culture and stains for both bacteria and fungi [68, 69]. Zhao et al. reported significantly higher positive detection rate of PCR for fungal keratitis (84.5%) as compare to the positivity rate for culture (35.3%) and stain (64.7%) [69]. A higher sensitivity of PCR for infectious keratitis compared to culture (98% versus 47%), but a slightly lower specificity (83% versus 100%) is reported in this study [69].
The PCR is rapid test, it takes 4–8 h, and only a small clinical sample is needed for diagnosis
Metagenomic deep sequencing (MDS) is a new technique for the diagnosis of FK; with next generation sequencing rapid and accurate diagnosis is possible. Next generation sequencing is high-throughput sequencing methods where billions of nucleic acid fragments can be sequenced simultaneously and independently. MDS is an unbiased approach that interrogates all genomes in a clinical sample and identify any organism whereas PCR is a targeted test the clinician must know the suspected causative organism.
It has been shown to enhance detection of common and unusual pathogens from the intraocular fluid of patients with infectious uveitis and other systemic infections [70, 71, 72]. A study by Seitzman et al. in a case series of nine patients of infectious keratitis diagnosed by conventional methods reported that MDS detected all the microorganisms identified by culture or PCR. MDS was able to identify parasitic, fungal, bacterial, and viral infections as a single assay. The pathogenic organisms ranged in size from smaller genomes (
Polyenes (Amphotericin B and Natamycin) and azoles (fluconazole, itraconazole, ketoconazole, miconazole, voriconazole, and posaconazole) constitute two major classes of antifungal drugs used to treat ocular fungal infections including fungal keratitis. In Comparison to antibacterial agents, antifungals have a lower efficacy due to their mechanism of action (usually fungistatic, with dose dependent fungicidal action), lower tissue penetration, and the indolent nature of the fungal infection [74]. Still for the management of fungal keratitis, the traditional anti-fungal drugs like natamycin and fluconazole in topical and oral form are used most commonly. In recent years, other new drugs and drug delivery system to increase bioavailability of drugs have been evaluated. Anti-fungal agents are summarized in Table 1.
Agent | Route of administration/ Dose | Indication | Limitations |
---|---|---|---|
Amphotericin B | Topical 1.5-5 mg/ml *IS 5-10 μg *IC 5-10 μg/0.1 ml | First line therapy for Candida species. Good to moderate activity against filamentous fungi. Deep keratitis with partial response to topical therapy | Not commercially available. Side effects: cataract, transient iritis and corneal oedema |
Natamycin | Topical 5% (50 mg/ml) suspension | First choice for Fusarium, Good activity against Aspergillus, less effective against Candida species | Low corneal penetration |
Econazole | Topical 2% | Effective against Fusarium, Aspergillus, and Candida species | Not commercially available for ophthalmic use |
Miconazole | Topical 10 mg/ml *SC 1.2 to 10 mg | Effective against candida Adjuvant with topical therapy in patients with low compliance | Less effective than polyenes |
Ketoconazole | Topical 1-2% Oral 200-400 mg/day | Broad spectrum As an adjuvant in deep keratitis | Less effective systemic toxicity (gastric intolerance, hepatotxicity) |
Fluconazole | Topical 0.2 % SC 2 mg/1 ml Oral 100-400 mg/day oral | Effective against yeast, less effective against filamentous fungi Good intraocular penetration used as adjuvant with topical agents | Filamentous fungi exhibit resistance liver enzyme monitoring |
Itraconazole | Topical 1% Oral 200-400 mg/day | Effective against Aspergillus, Candida, less effective against Fusarium As adjuvant with topical therapy in deep keratitis/ intraocular involvement by yeasts | Less effective than natamycin Lower bioavailability, and penetration into ocular tissues than other azoles |
Voriconazole | Topical 1-2% IS 50 μg/0,1 m IC 50μg/0,1 m Oral 200 mg **BID | Broad spectrum, FK resistant to polyenes/ first-line triazoles. Deep keratitis and Intraocular involvement | Less effective than natamycin Side effects- blurred vision change in colour perception; liver enzyme monitoring during oral use |
Posaconazole | Topical 100 mg/ml; 40 mg/ml Oral 200 mg **QID/ 400 mg BID | Broad spectrum, FK resistant to polyenes/first-line triazoles. | Limited information |
Flucytosine | Topical 10 mg/ml | Synergistic effect with topical Amphotericin B in FK due to yeasts | Narrow spectrum/ low penetration into ocular tissues |
Capsofungin | Topical 0.5% | Yeasts resistant to polyenes and first-line triazoles | Limited information |
Micafungin | Topical 0.1% | Yeasts resistant to polyenes and first-line triazoles | Limited information |
Terbinafine | Topical 0.5 % Oral 250 mg/day | Active against Aspergillus, Fusarium, Scedosporium and Candida. | Limited information |
Summary of antifungal agents used in Fungal Keratitis.
IC: Intracameral, IS: Intrastromal, SC: Subconjunctival.
BID: Twice a day, QID: for times a day.
Natamycin is first antifungal agent approved for FK by Food and Drug Administration in the 1960s. After that, many antifungal agents have been evaluated, no single agent has emerged as the best and most cost effective agent [7]. Cochrane systematic review in 2008 and 2012, found no evidence that any single drug, or combination of drugs, is more effective in the management of fungal keratitis. The trials included in this review were of variable quality and were generally underpowered [75, 76].
Natamycin is a polyene antifungal drug, it binds preferentially to ergosterol on the fungal plasma membrane and causes localized membrane disruptions by altering membrane permeability. Natamycin is currently considered the most effective medication against Fusarium and Aspergillus [7]. Cochrane systematic review in 2015 found that there is evidence that natamycin is more effective than voriconazole in the treatment of fungal ulcers. However, the trials included in this review were of variable quality and were generally underpowered. Future research should evaluate treatment effects according to fungus species [77].
Several studies reported that fungal keratitis due to fusarium responded better to Natamycin as compare to itraconazole and voriconazole [77]. NTM is the treatment of choice for filamentous keratitis, especially that due to Fusarium species. However its poor penetration into corneal stroma, limits its use in deep stromal keratitis. In deep keratitis or with involvement of intraocular structures, natamycin should be associated with other antifungal agents using a different route of administration.
Amphotericin B is the first broad-spectrum antifungal agent, produced by the actinomycetes,
Amphotericin B has poor ocular penetration after intravenous administration and is toxic to human cells at a higher dose. Due to systemic (nephrotoxicity) and ocular toxicity (punctate epithelial erosions and greenish discoloration of the cornea), amphotericin B is not currently a first line agent in treating fungal keratitis. In a study, Morand K, et al. compared the commercial 0.15% Amphotericin B with a liposomal formulation and found that the liposomal form was more stable and less toxic. The liposomal formulation also increased the potential amount of loaded drug by 3-fold compared with the conventional form [78].
Fluconazole is a synthetic bistriazole available in oral, topical, and IV preparations. It has good intraocular penetration with low side effect. It shown to have excellent absorption from the gastrointestinal tract. Its plasma concentrations with oral use reach almost the same levels as with intravenous administration. Intraocular Penetration is effective, with aqueous concentrations similar to those in the plasma [74, 79]. Topical 0.2% fluconazole is effective against
Voriconazole, a newer-generation triazole, with excellent ocular penetration and broad spectrum. Most of fungal isolates commonly implicated in keratitis were found to be susceptible to voriconazole.
Voriconazole has been reported to be effective in the treatment of fungal keratitis caused by different species and in cases not responding to other antifungal like natamycin and amphotericin [79, 80, 81, 82, 83, 84, 85]. Voriconazole has good intraocular penetration following oral administration. Advantage of oral administration is that it may provide steadier drug levels at the site of infection. Theil et al. compared aqueous samples after topical and oral voriconazole found that topical administration of voriconazole resulted in highly variable aqueous concentrations with troughs well below the minimum inhibitory concentration at which 90% of fungal isolates are inhibited (MIC90). Whereas, oral voriconazole provided relatively constant therapeutic concentration [84]. Many case reports reported successful treatment with topical voriconazole in conjunction oral or intravenous voriconazole [85, 86].
Posaconazole is a new triazole, a synthetic structural analogue of itraconazole. It is available as an oral suspension (40 mg/ml), administered at a dose of 200 mg four times daily or 400 mg twice daily. Now also available as delayed release tablets (100 mg) and injection (18mg/ml). In vitro and in vivo studies showed that posaconazole has a broad spectrum against Candida spp.,
Evidence on its use in ocular infections is still limited, but initial results are encouraging. Sponsel et al. also describe a case of keratitis by
Echinocandins (caspofungin and micafungin) are semisynthetic lipopeptides act by inhibiting the synthesis of glucan in the fungal cell wall causing osmotic imbalance and cell lysis. Matsumoto et al. have reported successful use of topical 0.2% micafungin in cases of refractory fungal keratitis [92]. In another study by Matsumoto et al. usiing topical micafungin 1 mg/ml reported found an efficacy comparable or superior to fluconazole in the treatment of keratitis by
Surgical intervention may be an option for patients with refractory FK not responding to medical treatment and severe fungal infections. Penetrating keratoplasty is considered the most common surgical intervention for serious fungal keratitis and cases with perforation or impending perforation. Recent advances have added more options such as targeted drug delivery at the site of infection in the form of intrastromal injections, collagen cross-linking and rose Bengal aided photodynamic therapy.
The efficacy of topical, as well as systemic, voriconazole is well established. Intra stromal voriconazole has been found as an effective approach for targeted drug delivery in the management of deep FK not responding to standard topical therapy [95, 96, 97]. Targeted drug delivery overcomes the issue of poor bioavailability of drugs in cases of deep fungal keratitis. It provides a depot of drug, close to the infected area. However, risk of introducing a new infection, inadvertent anterior chamber entry while performing the procedure in a hazy cornea are associated.
Intracameral Amphotericin B is another approach for targeted drug delivery, indicated when medical treatment with topical and systemic antifungal has failed, especially in cases with deep mycosis, endothelial plaque and presence of hypopyon with inflammation of the anterior chamber. The concentration injected, ranges between 5 and 10 μg/0.1 ml [98, 99].
Penetrating Keratoplasty (PK) is indicated for treatment of refractory or severe fungal keratitis, corneal thinning and perforation in FK [100]. A retrospective study including 52 eyes which underwent PK for corneal perforations secondary to FK, reported improved visual acuity in 46 eyes (88.5%) and clear grafts in 44 eyes (84.6%) at final follow-up [101]. The common complications of PK are graft rejection, recurrence of infection, and secondary glaucoma. Following PK, oral and topical antifungal medications are usually continued for 2 weeks and if pathology reports presence of fungus on the margin of the cornea sample, treatment continues for 6–8 weeks.
Cyclosporine has been recommended after PK in cases of fungal keratitis as it has been suggested to have dual antifungal and anti-immune properties [102]. However; evidences at present are limited, further studies are required to evaluate the risk and benefit of cyclosporine patients undergoing corneal transplant for fungal keratitis.
Amniotic membrane transplantation (AMT) has emerged as an option to delay or prevent PK secondary to fungal keratitis. Amniotic membranes have been used to facilitate ocular surface reconstructions in other ocular surface conditions. AMT support re-epithelialization of tissue, and the active components present in the membrane like nerve growth factors are thought to reduce pain [103]. In a study, 23 culture-proven, acute fungal keratitis patients with non-healing corneal ulcers, or impending corneal perforation underwent AMT to prevent PK or to promote re-epithelialization. Following AMT, 25% of patients with persistent positive culture for fungus required PK. The final visual outcome was BCVA > 20/400. It improved in 17, did not changed in four and worsened in two patients [104].
In an inflamed eye, there is increased risk of infection to be introduced into the anterior chamber or vitreous after PK and the use of corticosteroids, to prevent corneal graft rejection, may increase the risk of recurrence of fungal infection. Delay in PK can avoid these complications.
Lamellar keratoplasty (LK) is emerged as an alternate surgical procedure for fungal keratitis in which only diseased layers of the corneal surface are excised and replaced by donor cornea. In a study from China, reported the leading indication for LK in 2008 was infectious keratitis, and fungal keratitis constituted 67% of the infectious keratitis cases [105]. In another study, 55 antifungal refractory patients underwent LK with intensive topical and oral antifungal medication. In 93% of the patients, the fungal infection was eradicated. The remaining four patients were treated by a secondary PK. Visual acuity ranged from 20/20 to 20/63 with a few complications after 6–18 months follow-up [106].
Corneal collagen cross-linking (CXL) has been found successful in halting the progression of keratoconus by using riboflavin and UV-A light. In recent years, role of CXL in infectious keratitis is investigated in several studies with conflicting results on the efficacy of CXL in infectious keratitis [107, 108, 109, 110, 111, 112, 113]. Specifically the term photoactivated chromophore cross-linking (PACK-CXL) is used for CXL to treat infectious keratitis [108].
CXL may act in cases of fungal keratitis by a direct antifungal effect and by halting the ongoing melting, thus helping to avoid emergency keratoplasty [109, 110, 111]. Said et al. found that although PACK-CXL did not shorten the time to corneal healing, it prevented corneal melting [107]. PACK-CXL is found to be useful in fungal keratitis [108, 109, 110]. Abbouda et al. reported halting of corneal melting with PACK-CXL in one case while the other developed perforation [112]. The safety of CXL is of concern because the ultraviolet (UV) -A could damage intraocular structures. Spoerl et al. analyzed the expected damage compared with acceptable damage thresholds. During standard CXL of a cornea with a 400-μm thickness, the irradiances of the UV light reaching the iris, lens, and retina are less than the damage thresholds, and only the microbes, the corneal endothelium, and the keratocytes are at risk [113]. Minor complications after CXL, like transient limbitis and a transient increase in the size of the hypopyon in the first 24 h after CXL reported to be regress subsequently [107].
Photodynamic therapy (PDT) has been used in treatment of choroidal neovascularization in age-related macular degeneration, corneal neovascularization and in infectious keratitis due to Acanthamoeba [114]. PDT involves the activation of photosensitizers using light of varying wavelengths. Rose Bengal photodynamic therapy (RB-PDT) involved a photochemical process using Rose Bengal, excited with green light (wavelength: 500–550 nm) to generate reactive oxygen species (ROS), which, react with various intracellular components to cause cell death. In an in vitro study, Arboleda et al. have demonstrated RB PDT to be successful in fungal keratitis [115].
In a pilot clinical study by Naranjo et al., RB-PDAT was performed in 18 patients with progressive infectious keratitis unresponsive to standard medical therapy. RB-PDAT was considered successful in 13 individuals, defined as control of infection without the need for a therapeutic PK [116]. Amescua G et al. in an vitro and in a case study evaluated the efficacy of rose bengal photodynamic antimicrobial therapy (PDAT). They found that Riboflavin CXL demonstrated no inhibition of fungal isolate growth, whereas rose bengal PDAT inhibited fungal isolate growth within the irradiation zone. In addition, a case with resistant fusarium keratitis was treated successfully [117].
In a study, the role of vitamin D receptor (VDR) in innate immunity being discovered, may be a new target of treatment that can be explored for FK [118].Liposomes-encapsulated mannan extracts from
Recently, many efforts have been made to improve topical ocular drug delivery by designing various novel drug delivery systems (NDDS), including liposomes, nanoparticles, nanoemulsions, nanosuspensions, micelles, nanofibers, etc.
Several in vitro and in vivo experimental studies have reported encouraging results with NDDS. In a study, the liposomal formulation of the antifungal drug voriconazole found to exhibit a sustained drug release profile, and an 8-fold increase in the amount of drug retained in the cornea after 1 hour of exposure compared with the conventional suspension formulation [121]. The nanoparticle formulation of amphotericin B showed a sustained and controlled drug release for up to 11 hours, while the conventional drug formulation (0.15%) released the entire drug in only 4 hours. Nanoparticle formulation has also shown better pharmacokinetic properties, including 1.5-fold increase in half-life compared to the conventional solution formulation [122]. The microemulsion formulations of fluconazole showed a controlled release profile, releasing 50–80% of the drug in 12 hours, compared to the conventional drug solution, which released almost the entire drug in the first 6 hours [123]. In future, these newer formulations can be very useful in management of fungal keratitis.
Antimicrobial peptides (AMPs) have significant potential for use as antimicrobial agents for ocular or other infections [124]. AMPs, also known as host defense peptides, are naturally produced, small, cationic, amphiphilic peptides ranging in length from 12 to 50 amino acids. They are present on the surfaces of the eyes and in tears. More than 500 AMPs have been reported, including large molecules (RNases and S100A proteins); small peptides α and β defensins in human cationic antibacterial protein (CAP) 18, and α 37 amino acids; proteins like lysozyme and peptidoglycan recognition protein with significant bactericidal activity. The cations carried by AMPs can bind to the anion surface of the bacterial plasma membrane, causing the perforation of cell membrane and subsequently microbial death. AMPs also prevent microbial adhesion to and access into host cells and cause digestion of fungal cell wall by lysozyme [124, 125].
In vitro studies have shown AMPs Pc-C and Pc-E reduced binding of
Early diagnosis and treatment of fungal keratitis remains a challenge. A better understanding of pathogenesis can broadened the approach to management. Recent advances in techniques such as in vivo confocal microscopy and the evolution of PCR and MDS can useful in rapid and accurate diagnosis. Newer antifungal agents and newer methods of targeted drug delivery system can be helpful in treating refractory cases and improving outcome. New evolving technique like PACK-CXL and RB-PDT can be useful as adjuvant therapy.
New researches are continue to investigate the new aspects of pathogenesis, to device the novel drug delivery system to overcome the poor ocular penetration of antifungal drugs and enhance their efficacy and evaluate newer antifungal drugs. In recent years focus on modifying the immune response to the infection, thereby reducing the corneal melting and scarring which lead to poor vision, may have the greatest potential to improve visual outcomes.
The authors declare no conflict of interest.
Multidrug resistance (MDR) is one of the major factors contributing to a failure of doxorubicin for cancer treatment. Typically, the loss of cell sensitivity to chemotherapy is not limit to only doxorubicin and anthracycline derivatives. The MDR phenomenon evidently extends across various structurally-unrelated anticancer drugs, regardless of their molecular targets [1, 2, 3]. Hence, MDR development in cancer cells can simultaneously reduce the effectiveness of several cytotoxic drugs, leading to chemotherapeutic failure. Consequently, patients need higher doses of the anticancer agents to achieve therapeutic success. Either intrinsic or acquired resistance to doxorubicin-based chemotherapy has been attributed to various mechanisms including high expression of the drug efflux transporters, alteration of cell cycle checkpoints and apoptotic signals, increased drug detoxification and DNA repair processes [4, 5, 6]. Regarding this, MDR reversal can be one of the strategic approaches to enhance the efficacy, without increased adverse events, of doxorubicin.
This chapter focused on the most studied drug efflux transporter P-glycoprotein (P-gp) and its role in doxorubicin resistance in chemotherapy. In addition, some strategic approaches to conquer P-gp-based MDR in cancer treatment were also described.
Drug transporters can be grouped, according to their transport direction, into uptake and efflux pumps. Most of the known efflux transporters particularly P-glycoprotein (P-gp or MDR1; encoded by
Among the ABC efflux transporters, P-gp is the first and most studied transporter for MDR development in chemotherapy and drug-transporter-related interaction issues. This transporter was first identified from its involvement with multidrug-resistance in cancer cells. Particularly, overexpression of P-gp in cancer cells, either intrinsic or acquired, has been strongly associated with MDR occurrence, thereby P-gp becomes a promising target for development of chemosensitizers.
P-gp (MW approximately 170 kDa) is a single polypeptide with 1280 amino acids arranging in two duplicated units of a 6 α-helix structure hydrophobic TMD with linkage to a hydrophilic NBD (Figure 1) [1, 2, 7]. These two TMD with the total of 12 helices forms together into one channel as the membrane crossing passage. A substrate binds to the drug-binding site in the TMD whereas an ATP binds to the NBD. After ATP binding, ATP undergoes hydrolysis into ADP for energy to activate P-gp action through protein conformational alteration [7, 8]. This transporter, then, is able to move its substrates across lipid bilayer structure of plasma membrane to extracellular environment.
The key ABC drug efflux transporters and their selected anticancer drug substrates.
P-gp is constitutively located in the apical surface of either epithelial or endothelial linings of various normal tissues/organs such as adrenal glands, intestine, liver, kidney, pancreas, placenta, capillary vessels in the brain and testes [2, 7, 8, 9, 10]. Some organs such as prostate, skin, heart and skeletal muscle have low constitutive expression of P-gp. It should be noting that expression level of P-gp varies in each organ. For example, the numbers of P-gp in colon and ileum are higher than those in jejunum, duodenum and stomach [11, 12]. The tissue distribution of P-gp indicates that this transporter normally serves as an intrinsic determinant of oral drug bioavailability and drug disposition [13, 14, 15, 16, 17, 18]. Intestinal P-gp can influence the absorptive amount of its drug substrates, except those in BCS class I (i.e., high permeability and high solubility drugs such as verapamil), into the body after orally taken [13, 19, 20, 21]. The constitutive expression of P-gp at the mucosal surface in the lower gastrointestinal (GI) tract (i.e. jejunum, ileum, and colon) may prevent an uptake of its substrate, and perhaps also facilitate GI excretion. Moreover, the interplay between P-gp and the major phase I drug metabolizing enzymes (e.g. cytochrome P450, CYP450) can be anticipated due to their substrate similarity [22]. As such, P-gp and CYP3A4 act in concert to affect metabolic biotransformation of their substrates such as paclitaxel in intestine and liver, influencing the oral drug bioavailability [22, 23, 24]. Localization of P-gp in the blood-organ barriers such as brain or testis prevents drug penetration into such organ systems such as brain, testes [13, 23, 25, 26]. The presence of P-gp on the brush border of nephron proximal tubule and hepatocytes involve with excretion of drugs and endogenous substrates into the urine and bile [13, 27]. To this end, P-gp can be considered as the protective mechanism against xenobiotics as well as pharmacokinetic influencer particularly on absorption, distribution and disposition.
Expression of P-gp at plasma membrane involves several cellular processes that linking to P-gp mRNA and protein expression. The regulatory mechanisms have been largely associated with (1) activation or inactivation of oncogenes (e.g., Ras, c-Raf) and transcriptional process, (2) MDR1 translation into P-gp and post translational modification, protein trafficking, and (3) P-gp turn over. It has been reported that the dysregulated microRNA levels (e.g., miR-21, -27a, -451, -130a, -298) could cause MDR development in various cancer cells [28, 29, 30, 31, 32, 33, 34]. For example, miR-130 was correlated to MDR1/P-gp overexpression, and cisplatin resistance in SKOV3/CIS cells [32]. Overexpression of miR-27a and miR-451 was linked to increased MDR1 expression and MDR phenotype in resistant cancer cells A2780DX5 and KB-V1 [28].
Overexpression of P-gp particularly in MDR phenomenon has been evidently connected to up-regulation of MDR1 gene through alteration of various signaling pathways and transcription factors. Example of the transcriptional factors involving in MDR1 transcription are nuclear factor-κB (NF-𝂻) [35, 36], Y-box binding protein-1 (YB-1) [37, 38], activator protein-1 (AP-1) [39], and hypoxia-inducible factor-1 (HIF-1) [38, 40]. The activities of these transcription factors have been linked to various signal transduction pathways, particularly the two major cell survival signaling cascades i.e. (1) the mitogen-activated protein kinase (MAPK) [37, 41], and (2) the phosphatidylinositol 3-kinase (PI3K) pathways [42, 43]. It has been shown that hyperactivation of either MAPK/ERK1/2 or PI3K/Akt/NF-𝂻 signaling pathways results in overexpression of P-gp in doxorubicin-resistant cells such as lung, breast and ovarian cancer cells [44, 45, 46, 47, 48, 49]. An up-regulation of P-gp expression in vincristine-resistant human gastric cancer cells was associated with activation of the p-38/MAPK pathway [50].
After activation and translocation into nucleus, transcription factors such as NF-kB and YB-1 (Y-box binding protein) bind to MDR1 promoter region, leading to initiation of MDR1 transcription. Increase in YB-1 nuclear activity is related to P-gp-mediated development of MDR in several cancers including breast cancer, lung cancer, ovarian cancer, colorectal cancer, prostate cancer and osteosarcoma [38]. In response to cell stress such as hyperthermia, viral infection and chemical assault, the survival Akt and MAPKs signaling would be activated, and subsequently increase YB-1 expression and translocation into nucleus for its MDR1-transcription activity [51]. Doxorubicin is a known P-gp inducer in various cancer cells. Doxorubicin up-regulates MDR1 gene expression via the MAPK/ERK1/2 signaling that linked to activation of YB-1 in B-cell lymphoma [37]. Moreover, upregulation of P-gp has been reported after prolonged exposure to various functional unrelated compounds, leading to the loss of drug efficacy and safety [52]. Examples of the known P-gp inducers include anticancer (e.g., cisplatin, doxorubicin, etoposide vinblastine), antidepressants (e.g., trazodone, St. John’s Wort), anticonvulsants (e.g., carbamazepine, phenytoin), anti-HIV (e.g., saquinavir, indinarvir, tenofovir), immunosuppressants (e.g., cyclosporine, tacrolimus), steroids (e.g., dexamethasone) [52, 53, 54]. It is worth noting that certain CYP450 inducers such as rifampin and St. John’s Wort are able to up-regulate P-gp expression, possible sharing through the PXR regulation [55, 56]. Prolonged exposure to rifampin and St. John’s Wort in human led to increased intestinal P-gp level, and increased digoxin absorption [57, 58]. Since, P-gp-mediated MDR in cancer is largely due to up-regulation of P-gp expression, better understanding of the signaling proteins and transcription factors will provide a promising targets in overcoming MDR for anticancer chemotherapy.
Overexpression of P-gp has been strongly correlated with chemo-resistance and cancer relapses in several cancer patients such as breast cancer, adult acute myeloid leukemia, pheochromocytoma patients, leading to poor prognosis from therapeutic failure in patients receiving chemotherapy [1, 59, 60, 61, 62]. Accordingly, P-gp is intrinsically expressed in various cancer types, particularly those derived from tissues with high basal MDR1 expression levels such as colon, kidney and liver tissues. Being a transmembrane efflux pump, P-gp serves as a cellular defense mechanism against drug assault by limiting intracellular drug accumulation up to toxic threshold level. Regarding this, the susceptibility of cancer to anticancer drugs being P-gp substrate varies, depending on intrinsic expressed P-gp levels. Certain types of cancers may be classified as poor responder showing their unresponsiveness to chemotherapy regimens containing P-gp substrates. For example, prostate cancer appears to be better responder to chemotherapy, as compared to colorectal or renal cancers [63, 64]. Moreover, some cancers such as leukemia, lymphoma and breast cancer having low levels of intrinsic P-gp expression, and thus initially respond well to chemotherapy. Later, after repeated treatment, the expression level of P-gp markedly increases, and those cancers display multi-drug resistance (MDR) phenotype [1, 65, 66]. This acquired MDR phenomenon can be viewed as cellular adaptive survival response to cytotoxic challenge.
Examples of substrates and modulators of P-gp are listed in Table 1.
Substrates (Anti-cancer drugs) | Inducers (Anti-cancer drugs) | P-gp modulators | |
---|---|---|---|
Direct inhibitors | Suppressors of expression | ||
Actinomycin D Colchicine Docetaxel Doxorubicin Daunorubicin Epirubicin Etoposide Idarubicin Imatinib Methotrexate Paclitaxel Teniposide Topotecan Vinblastine Vincristine | Daunorubicin Docetaxel Doxorubicin Flutamide Paclitaxel Vinblastine Vincristine | Small molecule inhibitors Cyclosporin A Verapamil VX-710 (Biricodar) Dexverapamil PSC833 (Valspodar) GF120918 (Elacridar) XR9576 (Tariquidar) LY335979 (Zosuquidar) Capsaisin Curcumin Limonin Piperine Quercetin Monoclonal antibodies MRK 16 MRK 17 UIC 2 | Small molecule inhibitors Curcumin Dasatinib Dexverapamil Reserpine Imatinib Nilotinib Sorafenib Trifluoperazine Toremifene PSC833 (Valspodar) RNA interference Antisense oligonucleotides |
Selected substrates, inducers and modulators of P-gp.
Human ABC efflux transporters demonstrate their broad substrate specificity toward structurally diverse lipophilic compounds. Most of their substrates are weakly amphipathic and hydrophobic planar structure with aromatic ring and positively charged nitrogen atom [52, 54, 67, 68]. Examples of P-gp substrates are anticancer drugs (vinca alkaloids, anthracyclines, and epipodophyllotoxins), cardiovascular drugs (e.g., digoxin, quinidine, talinolol, diltiazem, losartan, verapamil), anti-microbial agents (e.g., doxycycline, erythromycin, itraconazole, rifampin), anti-viral drugs (e.g., indinavir), anticonvulsants (e.g., phenytoin), acid blockers (e.g., cimetidine), immunosuppressants (e.g., cyclosporine, tacrolimus), steroids (e.g., aldosterone, cortisol, dexamethasone), opioids (loperamide, morphine).
Modulators suppress P-gp activity through either (1) direct inhibition of P-gp function by either competitive or non-competitive inhibitors; or (2) suppression of P-gp expression levels by interferences with either transcription, translation/post-translation, and degradation processes.
The direct inhibition of active P-gp can be attributed to the interaction between chemicals and P-gp at either TMB or NBD [67, 68, 69]. Any compound such as tyrosine Kinase Inhibitors interferes with ATP binding or hydrolysis in NBD site can reduce P-gp transport action [70]. Chemicals identified as small molecule P-gp inhibitors such as amiodarone, diltiazem, verapamil bind to substrate binding sites or allosteric sites in TMB, resulting in interference on substrate binding and transport. It has been reported that certain compounds such as cyclosporine A could exert their inhibitory action by interfering with substrate recognition and ATP hydrolysis [8, 67, 68, 69]. It is not surprising that these TMB type inhibitors and substrates share many common molecular features such as hydrophobic planar structure. In addition, due to the diversity in chemical structure of P-gp inhibitors, establishment of the structure activity relationship (SAR) of P-gp inhibitors is very challenging. The structure pattern of the inhibitors contains planar rings and basic nitrogen atom within an extended side chain of the aromatic ring. The presence of tertiary amino groups, in comparison with primary and secondary amine, increases the anti-MDR potency considerably. Furthermore, the presence of nitrogen atom in non-aromatic ring apparently increases inhibitory action of the compounds [71]. Examples of P-gp inhibitors are calcium channel blockers (verapamil, diltiazem), and various phytochemicals such as flavonoid and steroidal compounds (e.g., quercetin, resveratrol), indole alkaloids and polycyclic compounds (e.g., capsaicin, piperine, rhinacanthin C) [66, 72, 73, 74].
Ideally, the P-gp inhibitors should be potent and selective to P-gp function at target cells/tissues, with no systemic side effects. To date, there are four generations of small molecule inhibitors. The first generation inhibitors are known drug substrates of the ABC transporters such as verapamil, cyclosporine A, tamoxifen and quinidine [75]. They were not specifically designed to be P-gp inhibitors, and could not display good clinical outcomes in their MDR reversal activity. The clinical disappointment could be due to their weak inhibitory potency against the MDR transporters including P-gp, and their pharmacokinetic interactions with chemotherapeutic agents, leading to the need of high doses and intolerable adverse effects [1, 76]. Next, the second generation inhibitors such as valspodar (cyclosporine A derivative) were developed, based on structure activity relationships of the first generation compounds, in order to improve potency, specificity, and to reduce systemic toxicity. Although this group of inhibitors demonstrated their improvement in inhibitory potency, their clinical outcomes were still unsatisfied due to their pharmacokinetic interaction with the anti-cancer drugs via inhibition of cytochrome P450, and their severe toxicity [75, 77]. Subsequently, the third generation P-gp inhibitors such as elacridar, tariquidar and zosuquidar were developed in order to address the limitations of the second generation compounds. These inhibitors elicit no effect on CYP P450 metabolism, therefore they are unlikely to affect the plasma concentrations of anti-cancer drugs. They were also more potent and selective P-gp inhibitors, effectively working in nanomolar concentration range. However, the potent P-gp inhibitor tariquidar can be either substrate or inhibitor of P-gp depending on its given dose [78]. To date, the clinical efficacy for MDR reversal of this generation has yet completely satisfied, its effectiveness possibly also depends on given dosage and intrinsic tumor properties.
Currently, phytochemicals or natural compounds with MDR reversal activity have been subject of interest in searching for new effective chemo-sensitizer against cancer. This group of inhibitors obtained from natural sources is classified as the fourth generation inhibitor. Numerous phytochemical researches on pharmacological activities and pharmacokinetics have revealed that plant-based compounds elicit a broad spectrum of pharmacological actions such as anti-cancer, anti-oxidant, anti-microbial, anti-inflammation, etc. In addition, these plant-based compounds, depending upon its molecular structure, may interfere with P-gp and metabolizing enzymes, leading to the concerning issues in drug bioavailability and pharmacokinetic drug interactions. The advantages of the fourth generation inhibitors in part rely on their natural origin with long history of uses in dietary or health supplements and in traditional medicine. It may be able to presume that this group of inhibitors derived from known edible products possessed less toxicity and more tolerable than those of the previous generation compounds. Evidently, even vegetables (e.g., bitter melon), spices (e.g., black pepper, turmeric) or fruits (e.g., orange, grapefruit) also contain substances that could inhibit P-gp and other efflux transporters in the ABC superfamily [72, 73, 74, 75, 77, 79, 80, 81, 82]. Their competitive inhibition against the efflux transporters enhance cytotoxicity of anticancer drugs such as doxorubicin and vinblastine, leading to potential MDR reversal in various cancer cells. However, the inhibitory potency of these plant-based compounds against P-gp activity might be low. Their IC50 values obtained from the in vitro cell culture models appear to be in micromolar range. Thus, this group of inhibitors is unlikely a good MDR reversing agent through direct P-gp inhibition at MDR cancer cells in clinical setting. In addition, the interference of P-gp activity of these compounds in pharmacokinetic aspect may influence on P-gp-related ADME and bioavailability of chemotherapeutic drugs that concomitantly given. Nevertheless, the opportunities of further development into effective chemosensitizers cannot be excluded. Better understanding of QSAR may enable to facilitate chemical modification of these identified plant-based P-gp inhibitors to generate more potent and high selective P-gp inhibitors. Furthermore, several plant-based compounds (e.g, curcumin, resveratrol, quercetin) have been demonstrated their potential in down-regulation of P-gp and other key regulators in transporter-independent MDR mechanisms [75, 82, 83, 84, 85, 86].
In addition to small molecule inhibitors, monoclonal antibodies can be another alternative approach in inhibiting P-gp activity. Theoretically, any agents that specifically affect lipid-protein interactions or protein structure of targeted P-gp can be developed into P-gp inhibitor. Typically, monoclonal antibody can be developed to specifically recognize and bind to its target protein, leading to inhibition of changes in protein conformation. Regarding this, human P-gp-specific antibodies UIC2, MRK-16 and 4E3 reacted specifically to the extracellular loop of both halves of P-gp, and disabled P-gp transport activity [87]. Consequently, treatment cancer cells with these antibodies resulted in increased concentrations of anticancer drugs (e.g., vincristine, actinomycin D, doxorubicin, paclitaxel) within the cells, and improve drug effectiveness [87, 88, 89, 90, 91]. In athymic mice model, MRK16 was demonstrated its ability to significantly reduce tumor mass [92]. Further clinical studies of human P-gp-specific antibodies are needed to conduct in terms of safety and efficacy.
In addition to direct inhibition, reduction of P-gp activity can arise from decrease of protein expression at plasma membrane. Interference on transcription and translation of MDR1 gene, resulting in reduction of P-gp expression, can be another approach to overcome MDR in cancer. Several innovative tools targeting at MDR transcription or mRNA including small molecules, antisense oligonucleotides, hammerhead ribozymes and RNA interference strategies have been employed.
Application of microRNA and RNAi technologies with either small-interfering RNA (siRNA) or small hairpin RNA (shRNA) to specific silence MDR1 expression in cancer cells with MDR phenotype has been demonstrated their effectiveness in down-regulation of MDR1 and P gp expression with paralleled increases drug accumulation and improved sensitivity to treatment. MicroRNAs (miRNAs) are small non-coding RNA molecules that can inhibit ABCB1 mRNA translation processes [93, 94]. A number of miRNAs have been studied on their ability to down-regulate P-gp expression and restore cell sensitivity to P-gp drug substrates in drug resistant cells [34]. For example, miRNA-4539 could increase doxorubicin-mediated cell death in MDA-MB-231 breast cancer cells [93, 94].
The RNAi technologies involve either transient gene-silencing by siRNA or stable inhibition by MDR1 shRNA-transfected on plasmid DNA of MDR cancer cells. Treatment with siRNA against MDR1 increases drug-mediated cytotoxicity in various MDR cancer cells such as paclitaxel in MDR1 ovarian cancer cells and doxorubicin in doxorubicin-resistant breast cancer cells [95]. In addition, siRNA was able to significant reduced size of doxorubicin-resistant xenograft in a mouse model [96]. MDR1 ShRNA transfected in taxol-resistant human ovarian cancer cell line A2780 effectively down-regulated P-gp expression, and enhanced paclitaxel-mediated toxicity in this cells [97].
Selective suppression of P-gp/MDR1 expression with either microRNA or RNAi technologies offers the novel approach to specifically combat P-gp-based MDR in cancer, and re-sensitize the MDR cells to chemotherapeutic agents. However, for their therapeutic applications, there are several challenges required especially the effective miR/RNAi delivery to target cancer cells, design of expression vectors for shRNA, systemic stability and degradation, and safety of patients.
Numerous small molecules particularly those in the fourth generation of P-gp inhibitors such as curcumin, ginsenoside, quercetin and resveratrol have been demonstrated their ability to reduce P-gp function in the MDR cancer cells via down-regulation of P-gp expression [83, 84, 85]. By targeting at the signaling pathways related to transcription process of MDR1, several plant-based compounds suppress P-gp expression in the resistance cells and improve chemo-sensitivity to anticancer drugs. For instance, the P-gp modulating effect of asiatic acid, ginsenoside, isoquinoline alkaloids (e.g. cepharantine, tetrandine) resulted from their blockade of MAPK/ERK1/2 or PI3K/Akt pathways in MDR cancer cells [86, 98, 99, 100, 101]. Another isoquinoline alkaloid berberine inhibited P-gp expression and enhanced doxorubicin-mediated toxicity in MCF-7 cells through down-regulation of AMPK-HIF1α signaling cascade [102]. Anti-MDR property of natural curcuminoids (e.g., curcumin, bisdemethoxycurcumin) involved with inhibition of human MDR1 gene expression in MDR cervical carcinoma KB-V1 cells [103]. In addition, certain compounds such as a natural marine product Et743 inhibit MDR1 transcription via blocking its promoter activation [104].
Doxorubicin is one of the most effective cytotoxic anticancer drugs. This drug has been used for combating various types of cancers such as cancers of breast, ovary, prostate, stomach, thyroid; small cell cancer of lung; squamous cell cancer of head and neck; multiple myeloma; Hodgkin’s disease; lymphomas; acute lymphoblastic leukemia (ALL) and acute myeloblastic leukemia (AML). Unfortunately, the uses of doxorubicin can be limited because of its dose-related toxicity (e.g., nausea, vomiting, hair loss, leucopenia, cardiomyopathy, heart failure) and high MDR incidence [105, 106]. Despite the good clinical therapeutic responses are seen in patients receiving doxorubicin in the earliest stage of treatment, multi-drug resistance may later develop and lead to treatment failure.
One of the major mechanisms responsible for doxorubicin-induced MDR is up-regulation of MDR1/P-gp expression. Doxorubicin is an anthracycline derivative with a four-membered ring system containing an anthraquinone chromophore, and an aminoglycoside (Figure 1). This molecular structure accommodates its interaction with major MDR efflux transporters in the ABC superfamily proteins. It has been well established that doxorubicin and other anthracycline derivatives are P-gp substrates with ability to up-regulate P-gp/MDR1 expression after repeated exposure in various cancer cells such as breast and lung cancers as well as in vivo and in clinical settings [66, 107, 108]. For instance, lung perfusion with doxorubicin resulted in an increase of MDR1 RNA in patients with sarcoma pulmonary metastases [18]. The P-gp-overexpressed cancer cells would have intracellular doxorubicin concentration below its effective threshold level. Consequently, cancer cells increasingly survive from doxorubicin-mediated cytotoxity. In this circumstance, titrating dose up to overcome MDR may not enable to achieve a successful outcome due to dose-limiting toxicity. Because the adverse effects of doxorubicin and other anti-cancer drugs are mostly concentration-dependent, increasing doses can produce higher degree of severity and unendurable adverse events, leading to patient’s intolerability and even fatal outcome. Addition of other cytotoxic drugs into doxorubicin-based regimens may not also enable to obtain a chemotherapeutic success, if those drugs are also substrates of the MDR transporters.
Generally, clinical efficacy of doxorubicin depends on its pharmacokinetics after systemic exposure influencing (1) the therapeutic concentration at target organs, and (2) the homogeneity of drug distribution in the cancerous tissues particularly solid tumor. In addition, it is very critical that doxorubicin accumulates within the targeted cancer cells at the level greater than its cytotoxic threshold to elicit its pharmacological actions.
Doxorubicin is poorly absorbed through GI with low bioavailability (approximately 5%) after orally taken, due to its instability in stomach acidic pH and CYP450 biotransformation in liver. In addition, doxorubicin can induce cytotoxicity in normal tissue. Currently, doxorubicin is commercially available for cancer treatment in injection dosage form. Due to its lipophilicity, doxorubicin moves through plasma membrane into the cells via passive diffusion, and its extent of tissues/cellular permeation and cellular retention can be limit by the existence of efflux transporters particularly P-gp. Apparently, doxorubicin is extensively distributed to several organs such as liver, heart, kidney after injection. Being the efflux transporters, P-gp has a significant impact on doxorubicin distribution to certain target tissues such as brain, testes [109, 110]. Certain P-gp inhibitors such as PSC-833, piperine capsaicin, resveratrol, silymarin and quercetin were reported their influence on the pharmacokinetics and tissue distribution of doxorubicin in animal models [85, 110]. Capsaicin was reported to significantly increase the extent of doxorubicin accumulation in mice brain after iv injection probably through inhibition of P-gp at blood brain barrier [110]. In addition, piperine and capsaincin, through P-gp inhibition, reduced drug excretion into bile and urine, leading to increased drug levels in liver and kidney [110].
Critically, overexpression of P-gp on the plasma membrane of cancer cells is a major determinant in preventing intracellular doxorubicin accumulation up to its cytotoxic level. Doxorubicin resistant cancer cells clearly display significant lower intracellular doxorubicin retention with more tolerable to doxorubicin exposure than their parental sensitive cells [65, 66]. Thus, P-gp can be a potential therapeutic target for either MDR reversal or bio-enhancing effect in cancer therapy. The presence of P-gp modulators clearly demonstrates their abilities to restore doxorubicin-mediated killing effect in various cancer cells by increasing intracellular level of doxorubicin [66, 111]. Several plant-based compounds such as limonin, quercetin, resveratrol, curcumin and rhinacanthin-C at their non-cytotoxic concentration have been reported to significantly enhance doxorubicin-mediated cytotoxicity in various cancer resistance cells through modulation of P-gp function [66, 112]. These phytochemical P-gp modulators may suppress P-gp function either by direct inhibition of activity or down-regulation of protein expression.
Moreover, the influence of P-gp on clinical resistance to doxorubicin-based treatment has been reported in cancer patients [113, 114, 115, 116]. In order to improve drug efficacy and patient tolerability, several approaches targeting at the P-gp function and expression have been introduced to increase cellular doxorubicin drug level and restore drug sensitivity without the need of higher concentration or additional chemotherapeutic drugs in the therapeutic regimen.
Taken that doxorubicin is a known substrate of P-gp, the drug efflux transporters in the ATP binding cassette (ABC) family. Hence, any approaches target at the function of these transporters can be presumed to increase therapeutic success for doxorubicin-based chemotherapeutic regimens. Regarding this, the strategies are as follows:
Increases in dose of doxorubicin or number of cytotoxic drugs to achieve therapeutic success. This has not been a satisfactory approach due to drug toxicity and patients’ intolerability.
Utilization of P-gp modulators to inhibit either function or expression.
Development of better drug delivery platforms to bypass P-gp activity, leading to increase intracellular retention of doxorubicin within target cells.
The current MDR reversal strategy has been exploited P-gp modulators that either directly inhibit P-gp activity or down-regulate P-gp expression in order to restore cell chemo-sensitivity to doxorubicin [107]. With the encapsulation technology, P-gp modulators can be co-administered with doxorubicin in the same drug delivery platform, and enhance intracellular doxorubicin accumulation. This approach can be accomplished if the potent, non-cytotoxic P-gp modulators that specifically target at cancer cells are implemented. In addition, the P-gp modulators that also target at non-transporter based resistance such as activation of cellular survival pathways can exert potentially synergistic impact on MDR reversal effect and better response to doxorubicin treatment. Collectively, the combined doxorubicin and P-gp modulators with multiple-hit targets is a promising strategy to achieve chemotherapeutic efficacy without the need of high dose or additional cytotoxic drugs in the therapeutic regimen.
This approach aims to suppress P-gp activity at plasma membrane of target cancer cells. Several P-gp modulators in combination with anti-cancer drugs have been evaluated for safety and efficacy in clinical trials. The clinical outcomes from the first three generations of ABC inhibitors such as quinine, verapamil, cyclosporine-A, tariquitor, PSC 833, LY335979, and GF120918 were quite disappointed, partly because of their dose-limiting adverse events. Most of the P-gp inhibitors required high doses for their clinical MDR reversal effects. In addition, their interference on the P-gp or other ABC transporters at non-target tissues such as brain and kidney could adversely increase accumulation of cytotoxic drugs in these tissues.
The fourth generation of P-gp modulators which are mostly natural products have gained a great interest as potential chemosensitizers in MDR cancer treatment. The advantages of being natural products with long history of use are inclined to the known safety profiles in human and potential hit multiple targets that can restore cell sensitivity to doxorubicin. In addition to direct inhibition of P-gp activity, a number of the natural compounds at non-cytotoxic concentration elicit their chemo sensitizing effects through down-regulation of MDR1 and signaling proteins in cell adaptive survival mechanisms. The higher degree of synergism between doxorubicin and a P-gp modulator can be anticipated with potential therapeutic success. Synergistic outcomes between doxorubicin and natural compounds such as resveratrol, quercetin, silymarin, gallic acid, curcumin, epigallocatechin-3-gallate have been demonstrated in various cancer cell models [82, 83, 103, 111, 117, 118, 119, 120]. In addition to P-gp modulatory activity (inhibiting both P-gp function and expression), these natural compounds have a broad spectrum of pharmacological activities such as antioxidant, anticancer, anti-inflammation, possible through multiple signaling pathways. For example, the biological effects of curcumin have been related to multiple signaling pathways including NF-kB, Akt, MAPK, Nrf2, AMPK, JAK/STAT that involve in MDR1 expression, cell inflammation, and apoptosis [121]. Co-administration of doxorubicin and curcumin significantly improved doxorubicin-mediated cytotoxicity in vitro cell models and in vivo hepatic xenograft mice model, compared with doxorubicin alone [121, 122, 123, 124, 125].
In addition to chemical-based modulators, the uses of specific antibody against P-gp or RNA interference (RNAi) technology to silence P-gp expression may be effective approach to suppress P-gp activity and restore chemo-sensitivity to doxorubicin treatment. Clinical studies on these MDR reversing methods should be extensively conducted to support their uses and benefits in cancer patients.
This approach aims to develop targeted delivery platforms for improving the permeation of doxorubicin/P-gp modulators/ chemo-sensitizers (e.g., antibodies against ABCB1, siRNA) into target cancer cells, leading to an increased intracellular doxorubicin concentration [3, 89, 96, 126, 127, 128]. Various nano-drug delivery platforms such as polymeric and solid lipid nanoparticle (SLNs), liposomes, micelles, mesoporous silica nanoparticles, nanostructured lipid carriers, dendrimers have been constructed to better targeting drug delivery to site of action. This approach in couple with utilization of P-gp modulators can overcome MDR and enhance therapeutic efficacy of doxorubicin. Furthermore, with cancer-targeting ability, this target specific delivery would limit the adverse effect to normal tissues. With the encapsulation technology, nanoparticles (NPs) loaded with doxorubicin and P-gp modulators or other molecules (e.g., siRNAs) has been reported their effectiveness in target delivery into the cells. For examples, aerosol OT (AOT)-alginate NPs enhanced cellular delivery of doxorubicin in MCF-7 cells [129]. Lipid-modified dextran-based NPs loaded with doxorubicin and MDR1 siRNA significantly increased intracellular doxorubicin and reduced P-gp expression levels in osteosarcoma cell line, as compared to doxorubicin alone [130]. Doxorubicin-curcumin composite NPs (e.g., NanoDoxCurc, pegylated-DOX-CUR NPs) could enhance effects of doxorubicin both in vitro and in vivo models of DOX-resistant cancers (e.g., multiple myeloma, acute leukemia, prostate and ovarian cancers). In addition, doxorubicin-curcumin NPs did not cause cardiac toxicity and bone marrow suppression in mice model [131].
Doxorubicin is an effective anti-cancer drug that has high MDR incidence. High expression of an efflux transporter P-gp is one established mechanism responsible for the loss of drug effectiveness and MDR development. This can be due to the P-gp function in preventing intracellular accumulation of doxorubicin up to its effective level. Several approaches have been introduced in order to increase the efficacy of doxorubicin-based chemotherapy and overcome MDR. The combination of doxorubicin and non-cytotoxic P-gp modulators, particularly when given to the specific target cancer can be a promising approach to increase cancer sensitivity to doxorubicin through suppression of P-gp function. With the novel encapsulation technologies, it is very possible to develop the drug delivery platforms with specific targeted cancer cells as well as improvement of doxorubicin delivery into the cells. By these means, enhancement of doxorubicin-mediated cytotoxicity can be achieved with minimal dosing of the anti-cancer drugs. After clinically approval, it will provide a great benefit to patients receiving doxorubicin-based chemotherapy.
The author gratefully thanks IntechOpen Limited for the sponsorship program in publishing this work.
The Author declares no conflicts of interest.
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His studies in robotics lead him not only to a PhD degree but also inspired him to co-found and build the International Journal of Advanced Robotic Systems - world's first Open Access journal in the field of robotics.",institutionString:null,institution:{name:"TU Wien",country:{name:"Austria"}}},{id:"441",title:"Ph.D.",name:"Jaekyu",middleName:null,surname:"Park",slug:"jaekyu-park",fullName:"Jaekyu Park",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/441/images/1881_n.jpg",biography:null,institutionString:null,institution:{name:"LG Corporation (South Korea)",country:{name:"Korea, South"}}},{id:"465",title:"Dr.",name:"Christian",middleName:null,surname:"Martens",slug:"christian-martens",fullName:"Christian Martens",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Rheinmetall (Germany)",country:{name:"Germany"}}},{id:"479",title:"Dr.",name:"Valentina",middleName:null,surname:"Colla",slug:"valentina-colla",fullName:"Valentina Colla",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/479/images/358_n.jpg",biography:null,institutionString:null,institution:{name:"Sant'Anna School of Advanced Studies",country:{name:"Italy"}}},{id:"494",title:"PhD",name:"Loris",middleName:null,surname:"Nanni",slug:"loris-nanni",fullName:"Loris Nanni",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/494/images/system/494.jpg",biography:"Loris Nanni received his Master Degree cum laude on June-2002 from the University of Bologna, and the April 26th 2006 he received his Ph.D. in Computer Engineering at DEIS, University of Bologna. On September, 29th 2006 he has won a post PhD fellowship from the university of Bologna (from October 2006 to October 2008), at the competitive examination he was ranked first in the industrial engineering area. He extensively served as referee for several international journals. He is author/coauthor of more than 100 research papers. He has been involved in some projects supported by MURST and European Community. His research interests include pattern recognition, bioinformatics, and biometric systems (fingerprint classification and recognition, signature verification, face recognition).",institutionString:null,institution:null},{id:"496",title:"Dr.",name:"Carlos",middleName:null,surname:"Leon",slug:"carlos-leon",fullName:"Carlos Leon",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Seville",country:{name:"Spain"}}},{id:"512",title:"Dr.",name:"Dayang",middleName:null,surname:"Jawawi",slug:"dayang-jawawi",fullName:"Dayang Jawawi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Technology Malaysia",country:{name:"Malaysia"}}},{id:"528",title:"Dr.",name:"Kresimir",middleName:null,surname:"Delac",slug:"kresimir-delac",fullName:"Kresimir Delac",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/528/images/system/528.jpg",biography:"K. Delac received his B.Sc.E.E. degree in 2003 and is currentlypursuing a Ph.D. degree at the University of Zagreb, Faculty of Electrical Engineering andComputing. His current research interests are digital image analysis, pattern recognition andbiometrics.",institutionString:null,institution:{name:"University of Zagreb",country:{name:"Croatia"}}},{id:"557",title:"Dr.",name:"Andon",middleName:"Venelinov",surname:"Topalov",slug:"andon-topalov",fullName:"Andon Topalov",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/557/images/1927_n.jpg",biography:"Dr. Andon V. Topalov received the MSc degree in Control Engineering from the Faculty of Information Systems, Technologies, and Automation at Moscow State University of Civil Engineering (MGGU) in 1979. He then received his PhD degree in Control Engineering from the Department of Automation and Remote Control at Moscow State Mining University (MGSU), Moscow, in 1984. From 1985 to 1986, he was a Research Fellow in the Research Institute for Electronic Equipment, ZZU AD, Plovdiv, Bulgaria. In 1986, he joined the Department of Control Systems, Technical University of Sofia at the Plovdiv campus, where he is presently a Full Professor. He has held long-term visiting Professor/Scholar positions at various institutions in South Korea, Turkey, Mexico, Greece, Belgium, UK, and Germany. And he has coauthored one book and authored or coauthored more than 80 research papers in conference proceedings and journals. 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Rahimi",authors:[{id:"38310",title:"Dr.",name:"Stefano",middleName:null,surname:"Carruba",slug:"stefano-carruba",fullName:"Stefano Carruba"},{id:"42459",title:"Prof.",name:"Cesare",middleName:null,surname:"Perotti",slug:"cesare-perotti",fullName:"Cesare Perotti"},{id:"42460",title:"Dr.",name:"Marco",middleName:null,surname:"Rinaldi",slug:"marco-rinaldi",fullName:"Marco Rinaldi"},{id:"42465",title:"Dr.",name:"Giuseppe",middleName:null,surname:"Bertozzi",slug:"giuseppe-bertozzi",fullName:"Giuseppe Bertozzi"},{id:"42466",title:"Dr.",name:"Luca",middleName:null,surname:"Feltre",slug:"luca-feltre",fullName:"Luca Feltre"},{id:"42467",title:"Dr.",name:"Mashallah",middleName:null,surname:"Rahimi",slug:"mashallah-rahimi",fullName:"Mashallah Rahimi"}]},{id:"60049",doi:"10.5772/intechopen.75493",title:"GNSS Error Sources",slug:"gnss-error-sources",totalDownloads:3187,totalCrossrefCites:19,totalDimensionsCites:32,abstract:"This chapter discusses the most serious sources of error affecting global navigation satellite systems (GNSS) signals, classifying these in a new way, according to their nature and/or effects. For instance, errors due to clock bias or drift are grouped together. Errors related to the signal propagation medium, too, are treated in the same way. GNSS errors need to be corrected to achieve accepted positioning and navigational accuracy. We provide a theoretical description for each source, supporting these with diagrams and analytical figures where possible. Some common metrics to measure the magnitude of GNSS errors, including the user equivalent range error (UERE) and the dilution of precision (DOP), are also presented. The chapter concludes with remarks on the significance of the sources of error.",book:{id:"6540",slug:"multifunctional-operation-and-application-of-gps",title:"Multifunctional Operation and Application of GPS",fullTitle:"Multifunctional Operation and Application of GPS"},signatures:"Malek Karaim, Mohamed Elsheikh and Aboelmagd Noureldin",authors:[{id:"227711",title:"Mr.",name:"Malek",middleName:null,surname:"Karaim",slug:"malek-karaim",fullName:"Malek Karaim"},{id:"240292",title:"Prof.",name:"Aboelmagd",middleName:null,surname:"Noureldin",slug:"aboelmagd-noureldin",fullName:"Aboelmagd Noureldin"},{id:"243124",title:"Dr.",name:"Mohamed",middleName:null,surname:"Elsheikh",slug:"mohamed-elsheikh",fullName:"Mohamed Elsheikh"}]}],mostDownloadedChaptersLast30Days:[{id:"71931",title:"Open Pit Mining",slug:"open-pit-mining",totalDownloads:1701,totalCrossrefCites:1,totalDimensionsCites:1,abstract:"Open pit mining method is one of the surface mining methods that has a traditional cone-shaped excavation and is usually employed to exploit a near-surface, nonselective and low-grade zones deposits. It often results in high productivity and requires large capital investments, low operating costs, and good safety conditions. The main topics that will be discussed in this chapter will include an introduction into the general features of open pit mining, ore body characteristics and configurations, stripping ratios and stripping overburden methods, mine elements and parameters, open pit operation cycle, pit slope angle, stability of mine slopes, types of highwall failures, mine closure and reclamation, and different variants of surface mining methods including opencast mining, mountainous mining, and artisan mining.",book:{id:"8620",slug:"mining-techniques-past-present-and-future",title:"Mining Techniques",fullTitle:"Mining Techniques - Past, Present and Future"},signatures:"Awwad H. Altiti, Rami O. Alrawashdeh and Hani M. Alnawafleh",authors:[{id:"313182",title:"Prof.",name:"Rami",middleName:null,surname:"Alrawashdeh",slug:"rami-alrawashdeh",fullName:"Rami Alrawashdeh"},{id:"313522",title:"Dr.",name:"Awwad",middleName:null,surname:"Altiti",slug:"awwad-altiti",fullName:"Awwad Altiti"},{id:"313523",title:"Prof.",name:"Hani",middleName:null,surname:"Alnawafleh",slug:"hani-alnawafleh",fullName:"Hani Alnawafleh"}]},{id:"64027",title:"Stages of a Integrated Geothermal Project",slug:"stages-of-a-integrated-geothermal-project",totalDownloads:4461,totalCrossrefCites:3,totalDimensionsCites:4,abstract:"A geothermal project constitutes two big stages: the exploration and the exploitation. Each one has a single task whose results allow defining the feasibility of a geothermal project, until achieving the construction and operation stage of the power generation plant. The first stage contains the area recognition, its limitation to the target, and elimination of external factors until defining a geothermal zone with characteristics to be commercially exploited. The main studies and analysis that can be applied during the exploration stage are listed, and the major indicator to continue with the project or suspend is the prefeasibility report. The major risks in the exploration stage are due to studies that are carried out on the surface; at this stage, the costs can be considered low. The main results of the exploration are the selection of sites to drill three or four initial wells. Each well provides a direct overview of the reservoir: depth, production thicknesses, thermodynamic parameters, and production characteristics. The drilling of three to four exploratory wells is recommended, as far as there is certainty of the feasibility of the project, and the development of the field begins with drilling of sufficient wells to feed the plant. In this stage, the cost increases, but the risks decrease.",book:{id:"7504",slug:"renewable-geothermal-energy-explorations",title:"Renewable Geothermal Energy Explorations",fullTitle:"Renewable Geothermal Energy Explorations"},signatures:"Alfonso Aragón-Aguilar, Georgina Izquierdo-Montalvo,\nDaniel Octavio Aragón-Gaspar and Denise N. Barreto-Rivera",authors:[{id:"258358",title:"Dr.",name:"Alfonso",middleName:null,surname:"Aragón-Aguilar",slug:"alfonso-aragon-aguilar",fullName:"Alfonso Aragón-Aguilar"}]},{id:"63059",title:"Generation, Evolution, and Characterization of Turbulence Coherent Structures",slug:"generation-evolution-and-characterization-of-turbulence-coherent-structures",totalDownloads:3705,totalCrossrefCites:3,totalDimensionsCites:4,abstract:"Turbulence stands as one of the most complicated and attractive physical phenomena. The accumulated knowledge has shown turbulent flow to be composed of islands of vortices and uniform-momentum regions, which are coherent in both time and space. Research has been concentrated on these structures, their generation, evolution, and interaction with the mean flow. Different theories and conceptual models were proposed with the aim of controlling the boundary layer flow and improving numerical simulations. Here, we review the different classes of turbulence coherent structures and the presumable generation mechanisms for each. The conceptual models describing the generation of turbulence coherent structures are generally classified under two categories, namely, the bottom-up mechanisms and the top-down mechanisms. The first assumes turbulence to be generated near the surface by some sort of instabilities, whereas the second assigns an active role to the large outer layer structures, perhaps the turbulent bulges. Both categories of models coexist in the flow with the first dominating turbulence generation at low Reynolds number and the second at high Reynolds number, such as the case in the atmospheric boundary layer.",book:{id:"7214",slug:"turbulence-and-related-phenomena",title:"Turbulence and Related Phenomena",fullTitle:"Turbulence and Related Phenomena"},signatures:"Zambri Harun and Eslam Reda Lotfy",authors:[{id:"243152",title:"Dr.",name:"Zambri",middleName:null,surname:"Harun",slug:"zambri-harun",fullName:"Zambri Harun"},{id:"252195",title:"Dr.",name:"Eslam",middleName:null,surname:"Reda",slug:"eslam-reda",fullName:"Eslam Reda"}]},{id:"64562",title:"Electrical Resistivity Tomography: A Subsurface-Imaging Technique",slug:"electrical-resistivity-tomography-a-subsurface-imaging-technique",totalDownloads:3214,totalCrossrefCites:8,totalDimensionsCites:12,abstract:"Electrical resistivity tomography (ERT) is a popular geophysical subsurface-imaging technique and widely applied to mineral prospecting, hydrological exploration, environmental investigation and civil engineering, as well as archaeological mapping. This chapter offers an overall review of technical aspects of ERT, which includes the fundamental theory of direct-current (DC) resistivity exploration, electrode arrays for data acquisition, numerical modelling methods and tomographic inversion algorithms. The section of fundamental theory shows basic formulae and principle of DC resistivity exploration. The section of electrode arrays summarises the previous study on all traditional-electrode arrays and recommends 4 electrode arrays for data acquisition of surface ERT and 3 electrode arrays for cross-hole ERT. The section of numerical modelling demonstrates an advanced version of finite-element method, called Gaussian quadrature grid approach, which is advantageous to a numerical simulation of ERT for complex geological models. The section of tomographic inversion presents the generalised standard conjugate gradient algorithms for both the l1- and l2-normed inversions. After that, some synthetic and real imaging examples are given to show the near-surface imaging capabilities of ERT.",book:{id:"8361",slug:"applied-geophysics-with-case-studies-on-environmental-exploration-and-engineering-geophysics",title:"Applied Geophysics with Case Studies on Environmental, Exploration and Engineering Geophysics",fullTitle:"Applied Geophysics with Case Studies on Environmental, Exploration and Engineering Geophysics"},signatures:"Bing Zhou",authors:null},{id:"17670",title:"The Qatar–South Fars Arch Development (Arabian Platform, Persian Gulf): Insights from Seismic Interpretation and Analogue Modelling",slug:"the-qatar-south-fars-arch-development-arabian-platform-persian-gulf-insights-from-seismic-interpreta",totalDownloads:9043,totalCrossrefCites:17,totalDimensionsCites:42,abstract:null,book:{id:"1297",slug:"new-frontiers-in-tectonic-research-at-the-midst-of-plate-convergence",title:"New Frontiers in Tectonic Research",fullTitle:"New Frontiers in Tectonic Research - At the Midst of Plate Convergence"},signatures:"C.R. Perotti, S. Carruba, M. Rinaldi, G. Bertozzi, L. Feltre and M. Rahimi",authors:[{id:"38310",title:"Dr.",name:"Stefano",middleName:null,surname:"Carruba",slug:"stefano-carruba",fullName:"Stefano Carruba"},{id:"42459",title:"Prof.",name:"Cesare",middleName:null,surname:"Perotti",slug:"cesare-perotti",fullName:"Cesare Perotti"},{id:"42460",title:"Dr.",name:"Marco",middleName:null,surname:"Rinaldi",slug:"marco-rinaldi",fullName:"Marco Rinaldi"},{id:"42465",title:"Dr.",name:"Giuseppe",middleName:null,surname:"Bertozzi",slug:"giuseppe-bertozzi",fullName:"Giuseppe Bertozzi"},{id:"42466",title:"Dr.",name:"Luca",middleName:null,surname:"Feltre",slug:"luca-feltre",fullName:"Luca Feltre"},{id:"42467",title:"Dr.",name:"Mashallah",middleName:null,surname:"Rahimi",slug:"mashallah-rahimi",fullName:"Mashallah Rahimi"}]}],onlineFirstChaptersFilter:{topicId:"104",limit:6,offset:0},onlineFirstChaptersCollection:[{id:"82515",title:"A Review on Elemental and Isotopic Geochemistry",slug:"a-review-on-elemental-and-isotopic-geochemistry",totalDownloads:25,totalDimensionsCites:0,doi:"10.5772/intechopen.105496",abstract:"Geochemistry is the study of the development, and distribution of chemical elements on Earth, which are found in rock-forming minerals and their byproducts, as well as in living beings, water, and the environment. The elemental geochemical variation of sediments is used to recognize the mechanisms controlling the estuarine environment and serves as a baseline for assessing the environmental effect in the future. Geochemistry is a unique field that deals with the study of mineral deposits. It also addresses the interconnections between the structures of rock, soil, water, and air, which vary according to different places. Furthermore, groundwater is the solely accessible water supply in many desert basins, particularly in developing nations. Geochemical indicators are proper instruments for addressing a diversity of hydrological issues, particularly in arid and semi-arid settings. Thermodynamically, the fugacity of oxygen (fO2) in solid earth varies by many orders of magnitude. Enstatite chondrites can have high levels of hydrogen abundance, hydrogen, and nitrogen isotope compositions like those of the earth’s mantle. The chapter deals with the basic concept of geochemistry and its types, as well as the development of geochemistry. It also explains elemental and isotopes geochemistry, human health, and medical geochemistry.",book:{id:"11139",title:"Geochemistry and Mineral Resources",coverURL:"https://cdn.intechopen.com/books/images_new/11139.jpg"},signatures:"Riyam N. Khalef, Amal I. Hassan and Hosam M. Saleh"},{id:"81757",title:"Petroleum Geochemistry",slug:"petroleum-geochemistry",totalDownloads:36,totalDimensionsCites:0,doi:"10.5772/intechopen.104709",abstract:"Petroleum geochemistry has entered its second period of growth. The first period, largely associated with conventional oil and gas, occurred in the 70s and 80s when the classic works on source rock characterization, biomarkers, depositional systems, and petroleum generation, including kinetics and basin modeling were the focus. The second period began slightly after the turn of the century as a consequence of the “unconventional resource” revolution and the interest in distressed resources developed, the focus turned to non-hydrocarbon contaminants, new interest in hydrocarbon expulsion and retention, identification of tight rock pay zones, and the development of organic porosity. This chapter will discuss source rock characterization and formation, petroleum generation, expulsion, and retention, correlation among hydrocarbon accumulations and to their source rock(s), and organic porosity.",book:{id:"11139",title:"Geochemistry and Mineral Resources",coverURL:"https://cdn.intechopen.com/books/images_new/11139.jpg"},signatures:"Mei Mei and Barry Katz"},{id:"81773",title:"Proterozoic Newer Dolerite Dyke Swarm Magmatism in the Singhbhum Craton, Eastern India",slug:"proterozoic-newer-dolerite-dyke-swarm-magmatism-in-the-singhbhum-craton-eastern-india",totalDownloads:24,totalDimensionsCites:0,doi:"10.5772/intechopen.104833",abstract:"Precambrian mafic magmatism and its role in the evolution of Earth’s crust has been paid serious attention by researchers for the last four decades. The emplacement of mafic dyke swarms acts as an important time marker in geological terrains. Number of shield terrains throughout the world has been intruded by the Precambrian dyke swarms, hence the presence of these dykes are useful to understand the Proterozoic tectonics, magmatism, crustal growth and continental reconstruction. Likewise, the Protocontinents of Indian Shield e.g. Aravalli-Bundelkhand, Dharwar, Bastar, and Singhbhum Protocontinent had experienced the dyke swarm intrusions having different characteristics and orientations. In Singhbhum craton, an impressive set of mafic dyke swarm, called as Newer dolerite dyke swarm, had intruded the Precambrian Singhbhum granitoid complex through a wide geological period from 2800 to 1100 Ma. Present chapter focuses on the published results or conclusions of these dykes in terms of their mantle source characteristics, metasomatism of the mantle source, degree of crustal contamination and partial melting processes. Geochemical characteristics of these dykes particularly Ti/Y, Zr/Y, Th/Nb, Ba/Nb, La/Nb, (La/Sm)PM are similar to either MORB or subduction zone basalts that occur along the plate margin. The enriched LREE-LILE and depletion of HFSE especially Nb, P and Ti probably indicate generation of these dykes in a subduction zone setting.",book:{id:"11139",title:"Geochemistry and Mineral Resources",coverURL:"https://cdn.intechopen.com/books/images_new/11139.jpg"},signatures:"Akhtar R. Mir"},{id:"81610",title:"Prospectivity Mapping Using Stream Sediment Geochemistry along the Orange River Catchment for Base Metal, Prieska, Northern Cape, South Africa",slug:"prospectivity-mapping-using-stream-sediment-geochemistry-along-the-orange-river-catchment-for-base-m",totalDownloads:50,totalDimensionsCites:0,doi:"10.5772/intechopen.101785",abstract:"The Areachap Terrane, which is part of the Namaqua Sector of the Namaqua-Natal Belt in the Northern Cape Province, host volcanic-hosted Zn-Cu deposits at volcanic centres. The primary objective was to map Volcanogenic Massive Sulphide (VMS) mineralisation, determine the heavy metal contents of sediments, locate the source of anomalies and delineate targets for follow-up studies. Nine thousand three hundred and fourteen stream sediments samples collected were analysed using XRF. The element associated with their respective lithostratigraphy was calculated using spatial joint analysis tool. ArcGIS was used to display uni-elements maps and relevant multi-element maps. The delineated potential VMS mineralisation target is considered for further follow-up study. The M23 and M24 anomalies are delineated for Cu_Ni mineralisation. M23 and M24 anomalies are sourced from ultramafic debris transported from the Ghaap Group; however, this potential target will require follow-up studies for verification. The correlation between the Cu-Pb-Zn anomaly with alkali elements (Nb, Zr, Th, and U) and REEs (in Table 9) suggests there is a possibility that the M26–M29 anomaly is alkali-granitic genetic origin. The As, Ba, Ce, Cr, Cu, Hf, Nd, Ni, Rb, Sr., S, V, Zr and Zn contents showed a heterogeneous spatial distribution, reflected by high coefficient of variation and large standard deviation.",book:{id:"11139",title:"Geochemistry and Mineral Resources",coverURL:"https://cdn.intechopen.com/books/images_new/11139.jpg"},signatures:"Nthabiseng Mashale"},{id:"81376",title:"Geochemistry Applied to the Exploration of Mineral Deposits",slug:"geochemistry-applied-to-the-exploration-of-mineral-deposits",totalDownloads:36,totalDimensionsCites:0,doi:"10.5772/intechopen.103941",abstract:"Geochemistry can be applied to the exploration of mineral deposits, for which it is necessary to understand the fundamentals of geochemical prospecting, the geochemical dispersion of elements based on their chemical properties. This chapter presents the basics of geochemical prospecting including: element mobility depending on ionic potential, pH, and Eh, with examples of Cu mobility during supergenic alteration of a primary sulfide deposit, a brief overview of sampling/geochemical prospecting methods, as well as a case study of the geochemical prospecting study carried out in the vanadium (V), uranium (U), and zinc (Zn) sedimentary mineral deposit of Puyango, Ecuador, in which anomalous and subanomalous values were detected in rock samples of various pathfinder elements of V and U.",book:{id:"11139",title:"Geochemistry and Mineral Resources",coverURL:"https://cdn.intechopen.com/books/images_new/11139.jpg"},signatures:"John Luis Manrique Carreño"}],onlineFirstChaptersTotal:5},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:8,limit:8,total:0},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:90,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:107,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:33,numberOfPublishedChapters:330,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:14,numberOfPublishedChapters:145,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:9,numberOfPublishedChapters:139,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:122,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:112,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:21,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:10,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:"2753-6580",doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. The whole process of submitting an article and editing of the submitted article goes extremely smooth and fast, the number of reads and downloads of chapters is high, and the contributions are also frequently cited.",author:{id:"55578",name:"Antonio",surname:"Jurado-Navas",institutionString:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",slug:"antonio-jurado-navas",institution:{id:"720",name:"University of Malaga",country:{id:null,name:"Spain"}}}},{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}}]},series:{item:{id:"25",title:"Environmental Sciences",doi:"10.5772/intechopen.100362",issn:"2754-6713",scope:"\r\n\tScientists have long researched to understand the environment and man’s place in it. The search for this knowledge grows in importance as rapid increases in population and economic development intensify humans’ stresses on ecosystems. Fortunately, rapid increases in multiple scientific areas are advancing our understanding of environmental sciences. Breakthroughs in computing, molecular biology, ecology, and sustainability science are enhancing our ability to utilize environmental sciences to address real-world problems.
\r\n\tThe four topics of this book series - Pollution; Environmental Resilience and Management; Ecosystems and Biodiversity; and Water Science - will address important areas of advancement in the environmental sciences. They will represent an excellent initial grouping of published works on these critical topics.