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",isbn:"978-1-80356-966-6",printIsbn:"978-1-80356-965-9",pdfIsbn:"978-1-80356-967-3",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,isSalesforceBook:!1,isNomenclature:!1,hash:"f86a9f720cc3ac0f1c385d0367ea89b9",bookSignature:"Dr. Fiaz Ahmad and Prof. Muhammad Sultan",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11624.jpg",keywords:"Agricultural Waste, Reuse, Reduction, Soil Health, Recycling, Agriculture and Environment, Modelling and Simulation, Agro-Industrial Waste, Bioresource Processing, Processing and Management, Crop Residue, Forest Waste",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"April 8th 2022",dateEndSecondStepPublish:"June 16th 2022",dateEndThirdStepPublish:"August 15th 2022",dateEndFourthStepPublish:"November 3rd 2022",dateEndFifthStepPublish:"January 2nd 2023",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"22 days",secondStepPassed:!1,areRegistrationsClosed:!1,currentStepOfPublishingProcess:2,editedByType:null,kuFlag:!1,biosketch:"Dr. Fiaz Ahmad is a researcher in the field of Agricultural Engineering with fifteen years of field and academic experience, currently in charge of the Agricultural Machinery Design Laboratory at Bahauddin Zakariya University. He applied for two patents at the national level.",coeditorOneBiosketch:"A renowned researcher in the field of Agricultural Engineering with 14 years of academic experience at Bahauddin Zakariya University. Winner of various prestigious fellowships, awards, and research grants. Published 250+ articles along with several books and chapters. Guest editor of seven ISI-SCI journals for publishers like SAGE, MDPI, and Frontiers.",coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"338219",title:"Dr.",name:"Fiaz",middleName:null,surname:"Ahmad",slug:"fiaz-ahmad",fullName:"Fiaz Ahmad",profilePictureURL:"https://mts.intechopen.com/storage/users/338219/images/system/338219.png",biography:"Dr. Fiaz Ahmad is an assistant professor and lecturer at the Department of Agricultural Engineering, Bahauddin Zakariya University, Multan, Pakistan. He obtained his Ph.D. in Agricultural Bioenvironmental and Energy Engineering from Nanjing Agriculture University, China, in 2015, and completed his postdoctorate in Agricultural Engineering from Jiangsu University, Zhenjiang, China, in 2020. He was awarded a fellowship from the Higher Education Commission of Pakistan for Ph.D. studies and from the Chinese Government for post-doctoral studies. He earned a BSc and MSc (Hons) in Agricultural Engineering from the University of Agriculture, Faisalabad, Pakistan, in 2004 and 2007, respectively. He is the author of more than fifty journal and conference articles. He has supervised six master’s students to date, and is currently supervising six master and two doctoral students. Dr. Ahmad has completed three research projects with his research interest focusing on the design of agricultural machinery, agricultural waste management, artificial intelligence (AI), and agricultural bioenvironment.",institutionString:"Bahauddin Zakariya University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"2",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"Bahauddin Zakariya University",institutionURL:null,country:{name:"Pakistan"}}}],coeditorOne:{id:"199381",title:"Prof.",name:"Muhammad",middleName:null,surname:"Sultan",slug:"muhammad-sultan",fullName:"Muhammad Sultan",profilePictureURL:"https://mts.intechopen.com/storage/users/199381/images/system/199381.png",biography:"Muhammad Sultan is an Assistant Professor at the Department of Agricultural\r\nEngineering, Bahauddin Zakariya University, Multan (Pakistan). He completed his Ph.D.\r\nand Postdoc from Kyushu University (Japan) in the field of Energy & Environmental\r\nEngineering. He was an awardee of MEXT and JASSO fellowships (from the Japanese\r\nGovernment) during Ph.D. and Postdoc studies, respectively. He also did a Postdoc as\r\na Canadian Queen Elizabeth Advance Scholar at Simon Fraser University (Canada) in\r\nthe field of Mechatronic Systems Engineering. He worked for Kyushu University\r\nInternational Institute for Carbon-Neutral Energy Research (WPI-I2CNER) for two years.\r\nCurrently, he is working on 4 research projects funded by the Higher Education\r\nCommission (HEC) of Pakistan. He has completed six projects in past in the field of\r\nagricultural engineering. He has supervised 10+ M.Eng. and Ph.D. thesis and 10+\r\nstudents are currently working under his supervision. He has published 120+ journal\r\narticles, 100+ conference articles, 13 book chapters, and 6 books. He is serving as guest\r\neditor for the journals like Sustainability (MDPI), Agriculture (MDPI), Energies (MDPI),\r\nAdvances in Mechanical Engineering (SAGE), Frontiers in Mechanical Engineering, and\r\nEvergreen Journal of Kyushu University. His research is focused on developing energy-\r\nefficient temperature and humidity control systems for agricultural storage, greenhouse,\r\nlivestock, and poultry applications. His research keywords include desiccant air-\r\nconditioning, evaporative cooling, adsorption heat pump, Maisotsenko cycle (M-cycle),\r\nenergy recovery ventilators; adsorption desalination; wastewater treatment.",institutionString:"Bahauddin Zakariya University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"5",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Bahauddin Zakariya University",institutionURL:null,country:{name:"Pakistan"}}},coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"5",title:"Agricultural and Biological Sciences",slug:"agricultural-and-biological-sciences"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"440212",firstName:"Elena",lastName:"Vracaric",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/440212/images/20007_n.jpg",email:"elena@intechopen.com",biography:"As an Author Service Manager, my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. Whether that be identifying an exceptional author and proposing an editorship collaboration, or contacting researchers who would like the opportunity to work with IntechOpen, I establish and help manage author and editor acquisition and contact."}},relatedBooks:[{type:"book",id:"6418",title:"Hyperspectral Imaging in Agriculture, Food and Environment",subtitle:null,isOpenForSubmission:!1,hash:"9005c36534a5dc065577a011aea13d4d",slug:"hyperspectral-imaging-in-agriculture-food-and-environment",bookSignature:"Alejandro Isabel Luna Maldonado, Humberto Rodríguez Fuentes and Juan Antonio Vidales Contreras",coverURL:"https://cdn.intechopen.com/books/images_new/6418.jpg",editedByType:"Edited by",editors:[{id:"105774",title:"Prof.",name:"Alejandro Isabel",surname:"Luna Maldonado",slug:"alejandro-isabel-luna-maldonado",fullName:"Alejandro Isabel Luna Maldonado"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10359",title:"Landraces",subtitle:"Traditional Variety and Natural Breed",isOpenForSubmission:!1,hash:"0600836fb2c422f7b624363d1e854f68",slug:"landraces-traditional-variety-and-natural-breed",bookSignature:"Amr Elkelish",coverURL:"https://cdn.intechopen.com/books/images_new/10359.jpg",editedByType:"Edited by",editors:[{id:"231337",title:"Dr.",name:"Amr",surname:"Elkelish",slug:"amr-elkelish",fullName:"Amr Elkelish"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1591",title:"Infrared Spectroscopy",subtitle:"Materials Science, Engineering and Technology",isOpenForSubmission:!1,hash:"99b4b7b71a8caeb693ed762b40b017f4",slug:"infrared-spectroscopy-materials-science-engineering-and-technology",bookSignature:"Theophile Theophanides",coverURL:"https://cdn.intechopen.com/books/images_new/1591.jpg",editedByType:"Edited by",editors:[{id:"37194",title:"Dr.",name:"Theophile",surname:"Theophanides",slug:"theophile-theophanides",fullName:"Theophile Theophanides"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3161",title:"Frontiers in Guided Wave Optics and Optoelectronics",subtitle:null,isOpenForSubmission:!1,hash:"deb44e9c99f82bbce1083abea743146c",slug:"frontiers-in-guided-wave-optics-and-optoelectronics",bookSignature:"Bishnu Pal",coverURL:"https://cdn.intechopen.com/books/images_new/3161.jpg",editedByType:"Edited by",editors:[{id:"4782",title:"Prof.",name:"Bishnu",surname:"Pal",slug:"bishnu-pal",fullName:"Bishnu Pal"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3092",title:"Anopheles mosquitoes",subtitle:"New insights into malaria vectors",isOpenForSubmission:!1,hash:"c9e622485316d5e296288bf24d2b0d64",slug:"anopheles-mosquitoes-new-insights-into-malaria-vectors",bookSignature:"Sylvie Manguin",coverURL:"https://cdn.intechopen.com/books/images_new/3092.jpg",editedByType:"Edited by",editors:[{id:"50017",title:"Prof.",name:"Sylvie",surname:"Manguin",slug:"sylvie-manguin",fullName:"Sylvie Manguin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"371",title:"Abiotic Stress in Plants",subtitle:"Mechanisms and Adaptations",isOpenForSubmission:!1,hash:"588466f487e307619849d72389178a74",slug:"abiotic-stress-in-plants-mechanisms-and-adaptations",bookSignature:"Arun Shanker and B. Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"72",title:"Ionic Liquids",subtitle:"Theory, Properties, New Approaches",isOpenForSubmission:!1,hash:"d94ffa3cfa10505e3b1d676d46fcd3f5",slug:"ionic-liquids-theory-properties-new-approaches",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/72.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"314",title:"Regenerative Medicine and Tissue Engineering",subtitle:"Cells and Biomaterials",isOpenForSubmission:!1,hash:"bb67e80e480c86bb8315458012d65686",slug:"regenerative-medicine-and-tissue-engineering-cells-and-biomaterials",bookSignature:"Daniel Eberli",coverURL:"https://cdn.intechopen.com/books/images_new/314.jpg",editedByType:"Edited by",editors:[{id:"6495",title:"Dr.",name:"Daniel",surname:"Eberli",slug:"daniel-eberli",fullName:"Daniel Eberli"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"57",title:"Physics and Applications of Graphene",subtitle:"Experiments",isOpenForSubmission:!1,hash:"0e6622a71cf4f02f45bfdd5691e1189a",slug:"physics-and-applications-of-graphene-experiments",bookSignature:"Sergey Mikhailov",coverURL:"https://cdn.intechopen.com/books/images_new/57.jpg",editedByType:"Edited by",editors:[{id:"16042",title:"Dr.",name:"Sergey",surname:"Mikhailov",slug:"sergey-mikhailov",fullName:"Sergey Mikhailov"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1373",title:"Ionic Liquids",subtitle:"Applications and Perspectives",isOpenForSubmission:!1,hash:"5e9ae5ae9167cde4b344e499a792c41c",slug:"ionic-liquids-applications-and-perspectives",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/1373.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"64918",title:"From the Origins of the Opioid Use (and Misuse) to the Challenge of Opioid-Free Pain Management in Surgery",doi:"10.5772/intechopen.82675",slug:"from-the-origins-of-the-opioid-use-and-misuse-to-the-challenge-of-opioid-free-pain-management-in-sur",body:'\nThe perception of pain is an integral part of human existence. Although uncomfortable to the individual, the perception of pain is necessary to protect the body from harm. A painful sensation causes man to seek an explanation for the reason of this discomfort. A brief history of the origins of pain and the development of pain medications is presented, followed by the current understanding of the physiology of pain and modern concern about opioid use. In the second half of the twentieth century, synthetic opioids were introduced to achieve hemodynamic stability during anesthesia. Furthermore, combined with hypnotics and muscle relaxants, the opioids administration is considered a keystone of anesthesia. For instance, a prevalence of 30% of unwanted effects of opioids such as nausea, vomiting, dizziness and constipation has been reported [1]. An increased occurrence of confusion and postoperative delirium [2], respiratory depression, increased postoperative pain and opioids consumption with abuse, immunodepression, hyperalgesia and chronic postoperative pain have also been described. Of note, opioid tolerance to analgesia can occur after a single dose. Thus, the management of pain in surgery is currently moving in the direction of the reduction of opioid use preoperatively, perioperatively, and postoperatively. The modern multimodal anesthesia and analgesia with intraoperative hemodynamic stability, immobility and anticipation of postoperative analgesia can be achieved without opioids. The concept of opioid-free anesthesia (OFA) is based on the idea that hemodynamic stability can be obtained without opioids during anesthesia. In particular, OFA is a fascinating multimodal approach to anesthesia which provides the combination of hypnotics, N-methyl-D-aspartate (NMDA) antagonists, local anesthetics, anti-inflammatory drugs and alpha-2 agonists such as dexmedetomidine, and no intra-operative systemic, neuraxial, or intracavitary opioid is administered during anesthesia and the perioperative course. This strategy is aimed to prevent postoperative opioid-related adverse effects and to enhance recovery after surgery.
\nEarly theories of the origin of pain, especially from internal diseases, revolved around demonic and religious beliefs. Shamans and sorcerers treated patients with the use of amulets, magic sculptures, talismans, magic ceremonies and rituals to ward off demons and evil spirits. It was believed that spirits and demons should leave the body from the same way it entered, resulting in cultural scarifications to allow bad fluids, spirits and demons to escape. In Egypt, religious ceremonies and prayers were believed to help relieve pain. Incantations to God Horus and other deities were thought to relieve unilateral headaches [3].
\nAncient cultures have used leaves of cocoa plant and opium for religious and medical purposes. The earliest anthropological evidence of the use of cocoa leaves was from the pre-Inca culture in Peru, dated to 1300 B.C. The Peruvians used cocoa leaves as a local anesthetic in trepanation operations. Opium was introduced to Egypt around 1500–1300 B.C., and was used as a cream for external application and for the fumigation of toothaches. In India and China, opium was used for the treatment of toothache and joint pain. In these cultures, opium could not be separated from its “recreational” use [3].
\nIn the seventeenth century, physicians began to consider the human body as a machine with different parts in constant motion. The French philosopher Rene Descartes proposed one of the earliest concepts of modern physiology: a movement or touch initiated at the peripheral nerve endings propagated to the brain. This concept, which formed the basis of nineteenth century pain theories, is illustrated by Descartes famous figure [3] of a boy, whose foot is being stimulated by heat from a fire. Several scientific discoveries followed Descartes physiologic concept of pain, including that of Sir Humphrey Davy’s reports of pain relief from inhalation of nitrous oxide in 1800 and James Moore’s report of opium use for postoperative analgesia in 1784 [3].
\nWith a better understanding of the physiology and pathways of pain, pharmacologic discoveries, particularly of morphine, were made in the beginning of the nineteenth century. The German pharmacist Friedrich Wilhelm Adam Ferdinand Serturner was the first to isolate morphine from poppy in 1805. He named the substance after Morpheus, the Greek god of sleep. The invention of the hypodermic hollow needles and syringes by Charles Gabriel Pravaz and Alexander Wood in the 1850s allowed the ease of subcutaneous application. While this helped the widespread use of morphine, it also paved way for the use and abuse of morphine that spread rapidly during the American Civil War (1861–1865) and the French-German War (1870–1871). Opioid addiction became known as the “soldier’s disease” and spurred research efforts to find substances with a lower risk of abuse [3].
\nStemming from the discovery of morphine, scientists began to experiment and develop different forms of morphine. In 1874 Charles Adler Wright synthesized diacetyl-morphine, which in 1898 was registered under the name of heroin. This drug showed stronger cough suppression but lower analgesic effects when compared to morphine in animal models. Toward the beginning of the twentieth century, addiction to heroin became a growing problem in the USA, and in 1914, the government began implementing stricter regulations, limiting the maximum amount of heroin in preparations. These regulations also prohibited opium, morphine, cocaine, and several other substances from non-prescription preparations [3].
\nThe development of new opioid analgesics continued. Derivatives of morphine and codeine such as hydromorphone, dihydrocodeine, hydrocodone, oxymorphone, meperidine, and oxycodone emerged at the beginning of the twentieth century. Methadone was developed during World War II in Germany and was used primarily as a substitution therapy in drug addicts. Methadone is a μ-receptor agonist and a noncompetitive NMDA antagonist. The NMDA receptor is involved in the pathophysiology of neuropathic pain. Fentanyl was developed by Paul A.J. Janssen in 1953 and was proved to be approximately 40 times more active than morphine. Subsequently, similar compounds with stronger potency developed, including carfentanil, sufentanil, and alfentanil [3].
\nThe techniques for pain relief, such as spinal cord analgesia, knee surgeries, and different routes of administration for medications, began to develop after further research suggested opioid receptors in the human brain and the demonstration of endogenous opioids, the endorphins and enkephalins, constituting an internal system of pain modulation. Opioid receptors were found in high density in the substantia gelatinosa of the spinal cord, as well as the limbic system and periaqueductal gray area of the brainstem. This led to the reintroduction of spinal opioid application in clinical medicine. Peripheral opioid receptors were demonstrated in the late 1980s, and Stein and colleagues showed reduced operative pain following arthroscopy of the knee joint following intraarticular injection of morphine. Sustained release formula and transdermal route of administration provided a profound impact on the management of chronic pain. It made pain management much more comfortable for the patients, resulting in an improved quality of life. Morphine was available in the sustained release formula in 1983, while fentanyl was available in the transdermal system. Various opioids in sustained release formula and transdermal systems followed [3].
\nSurgical anesthesia experimentations in the nineteenth century allowed for major development in pain-free surgeries. One of particular note was the Dr. William Morton’s experimentation with ether as a local anesthetic for a surgical neck operation. The dentist Horace Wells previously used gas during teeth extraction procedures. The first surgical ether anesthetized procedure was by the dentist William Thomas Green Morton at Massachusetts General Hospital, Boston, in 1846. Dr. John C. Warren was the senior surgeon operating on a congenital vascular tumor on the neck of a young man, Gilbert Abbott. To the audience’s amazement, Abbott did not cry out in pain during the procedure, and this ushered in the era of pain-free surgery [3]. Painters Warren and Lucia Prosperi were commissioned in 2000 to immortalize this milestone in anesthetic surgery with a painting that became known as the Ether Dome painting.
\nFurther significant steps in anesthesia in surgical environments continued. The use of chloroform in the management of childbirth was introduced into the medical world by Sir James Young Simpson in 1847, the same year physiologist Marie Jean Pierre Flourens had discovered the anesthetic properties of chloroform in animals. Chloroform remained the preferred anesthetic until the end of the nineteenth century even though the use of chloroform resulted in significantly more deaths than with ether [3].
\nCocaine in local anesthesia marked another milestone in the advancement of pain management in surgery. During the nineteenth century, Albert Niemann, a scientist from Gottingen, isolated cocaine out of the mixture of alkaloids of the cocoa plant. The extracts became popular for conditions such as toothaches, digestive disorders, hysteria, and melancholia, as well as for being an aphrodisiac. Carl Koller experimented with cocaine as a local anesthetic on frog eyes, other animals, his assistants, and even himself. His paper, which demonstrated cocaine’s efficacy, was presented at the Heidelberg Ophthalmological Society in 1884 by his colleague Josef Brettauer. The presentation was widely received and others began experimenting with cocaine’s surgical applications [3].
\nAfter the Heidelberg presentation, scientists began experimenting with cocaine as a nerve block, in advanced cancer patients, and in spinal cord operations. American surgeon William Steward Halsted [4] began experimenting with cocaine as a nerve block, which opened up new possibilities in surgery anesthetics. Halsted and several of his colleagues eventually became addicted to cocaine during their experimentations with the drug. James Leonard Corning used cocaine as a spinal anesthetic in 1885. Dr. Herbert Snow was the first physician to incorporate cocaine into cancer pain treatment. In 1896, he administered cocaine with opium for pain relief to patients with advanced diseases. He later developed the “Brompton Cocktail,” a mixture containing morphine, cocaine, and alcohol. German surgeon August Bier and his colleagues published their clinical results of spinal anesthesia, including intrathecal injections on each other. He introduced intravenous regional anesthesia in 1908. Rudolph Matas administered the first morphine anesthetic to the spinal cord in 1909. Most of the nerve blocking techniques during this time period were developed for surgical anesthesia [3].
\nFurther experimentation with cocaine as an analgesic continued during the nineteenth century, resulting in the development of new local anesthetics including synthetic substitutes. Alfred Einhorn synthesized procaine in 1905. Lofgren and Lundqvist synthesized Lignocaine in 1943. Other local anesthetics followed including cinchocaine and amethocaine in the 1920s, mepivacaine, prilocaine, and bupivacaine in the late 1950s, etidocaine in the 1970s, and ropivacaine in the 1980s [3].
\nThe current understanding of the physiology of pain involves the activation of the nervous system. Noxious stimuli, including intense thermal, mechanical, or chemical stimuli, are recognized by nociceptors in the peripheral nervous system. The threshold for pain activation is relatively high, requiring a large stimulus for signal propagation. The signals either travel through Aδ-fibers, Aβ-fibers, or C-fibers. While the Aδ-fibers and Aβ-fibers are myelinated and transmit “acute, well-localized, fast pain,” the C-fibers are unmyelinated and transmit “slow” pain, often described as an ache. The signals travel to the dorsal root ganglion, are transmitted through the spinal cord and synapse on the somatosensory cortex and limbic system. The modification of this pathway by medications aims to reduce or eliminate pain [5].
\nAlthough opioids have historically been significant medications in the management of pain, opioids have also been the source of significant public health concern because of the addictive and destructive adverse effects of the medication. During the twentieth century, there were positive attitudes for the use of opioids, as a letter written to the New England Journal of Medicine underscored the safety and low addictive potential of opioid use in chronic pain patients, with subsequent letters and reviews supporting this perspective. With the impression that there was very little risk, particularly of addictive potential, in prescribing opioids for chronic pain, the demand for opioid use increased in clinical settings. However, by 2000, attitudes are beginning to shift and a reduction of opioid use is becoming the trend [5].
\nThe detrimental overuse, abuse and addiction of opioids can precipitate from prolonged treatment of opioids. Opioid tolerance occurs when there is a reduction in the analgesic and sedative effects of these medications. Tolerance to the euphoric effects also develop, further increasing the risk of addiction. Opioid dependence results from the overactivation of the somatomotor cortex and autonomic nervous system due to the increased signaling of the cells while on the inhibitory medications. Cessation of opioid use or the administration of opioid receptor antagonists such as naloxone or naltrexone cause the withdrawal symptoms, including diarrhea, vomiting, agitation, hyperalgesia, hyperthermia, and hypertension [5].
\nIn the United States, the opioid abuse has reached epidemic proportions and have become a public health issue. The treatment of opioid dependence is unclear, but there have been significant public health prevention efforts to combat the trends of increased abuse and overdose deaths [5]. On the topic of opioid epidemic, the United States Surgeon General Dr. Jerome Adams supports overdose education and awareness, and suggests co-prescribing naloxone to patients on high morphine milligram equivalent who are at risk [6]. Nearly all the U.S. states have laws supporting naloxone provision to lay persons. Further, the U.S. Department of Health and Human Services highlighted naloxone rescue kit access and emergency overdose as a priority to address the opioid crisis. The benefits of naloxone programming have been demonstrated in San Francisco, as well as in North Carolina, where a 70% decline in prescription opioid-related overdose death rates was observed from 2009 to 2010 [7].
\nThe current trend in surgery is in the direction away from general anesthesia that traditionally requires opioids preoperatively, intraoperatively, and postoperatively, and toward a more multi-modal regimen approach with preoperatively patient education, specifically highlighting the interplay between opioids and the human body’s natural pain management system.
\nCurrently, many surgical operations have been traditionally performed under general anesthesia with adjunct opioid use. The main mechanism of action of opioids is the stimulation of μ receptors, which has inhibitory effects on the propagation of pain signals to the brain [8]. However, there are a wide variety of associated adverse effects of opioids including nausea, vomiting, constipation, postoperative sedation, dizziness, and addiction [9]. Opioid use also carries significant morbidity, prolong hospital stays, increase use of medications needed to reverse side effects, and decrease patient satisfaction [10, 11]. Further, opioids may also cause paradoxical hyperalgesia due to opioid-induced neural plasticity. This appears to affect both the central and peripheral nervous systems, and may lead to sensitization of the pain pathways [12].
\nIn addition to the wide variety of adverse effects, opioids use may also hamper the effects of the human body’s own natural pain killers, endorphins. Opioid administration reduces the production of beta-endorphins and impairs the function of mu-opioid receptors [13]. Beta-endorphins have significant natural analgesic effects and have been proposed to yield 18–33 times greater analgesic potency than morphine. Endorphin release is believed to enhance in response to a stressor, such as sharp pain, and can be quickly utilized to control the pain. The stressor causes the hypothalamus to release corticotrophin-releasing hormone (CRH), a peptide hormone and neurotransmitter, from the periventricular nucleus. CRH stimulates the cleavage of protein proopiomelanocortin (POMC) from basophilic cells, resulting in smaller proteins, one of them being beta-endorphin. In the peripheral nervous system, beta-endorphins bind to the μ receptors on both pre-synaptic and post-synaptic nerve terminals. The binding leads to the release of gamma-aminobutyric acid (GABA), which inhibits the release of substance P, a tachykinin protein involved in the transmission of pain. Endorphins not only have greater analgesic potency than morphine, but also enhances individuals’ mood and well-being, due to indirect elevation of dopamine [13]. In the central nervous system, beta-endorphins bind the μ receptors on the pre-synaptic nerve terminals and inhibit release of GABA, which normally inhibits the release of dopamine. The overall effect of beta-endorphins, which is decreased in opioid use, is a decrease in pain and an elevation in wellbeing.
\nOpioid-free anesthesia is an anesthetic technique without intraoperative systemic, neuraxial or intracavitary opioids, and that avoids perioperative opioids. There are a number of therapeutic uses and indications for opioid-free anesthesia including narcotic history (acute and chronic opioid addiction), opioid intolerance, morbidly obese patients with obstructive sleep apnea, hyperalgesia, history of chronic pain, immune deficiency, oncologic surgery, inflammatory disease, chronic obstructive pulmonary disease, and asthma [14].
\nPostoperative complications, such as respiratory depression, central muscle rigidity, pharyngeal muscle weakness, obstructed breathing, negative inotropism, nausea, vomiting, ileus and constipation, urinary retention, tolerance and addiction, dizziness, and excessive somnolence, can be reduced or prevented. Decrease histamine release (allergy/anaphylaxis), increase patient satisfaction, and enhanced recovery after surgery and anesthesia (ERAS) are other beneficial effects of opioid-free anesthesia [14, 15, 16].
\nOpioid-free anesthesia should be avoided in patients with allergy to any adjuvant drugs, and should be used cautiously in patients with disorders of autonomic failure, cerebrovascular disease, critical coronary stenosis, acute coronary ischemia, heart block, extreme bradycardia, non-stabilized hypovolemic shock or polytrauma patients, controlled hypotension for minimal blood loss, and elderly patients on beta-blockers.
\nInterest and use of adjuvant modalities, including ketamine, gabapentinoids, intravenous lidocaine, magnesium sulfate, alpha-2 adrenoreceptor agonists, and beta-blockers, is increasing because of enhanced recovery, particularly in specific patient populations like chronic pain and opioid dependent patients [15].
\nIn light of the serious adverse effects associated with opioids, many clinicians are forgoing prescribing opioids excessively and using opioid alternatives for postoperative pain control. These non-opioid alternatives, including acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDS)/cyclooxygenase-2 (COX-2) inhibitors, gabapentin, local anesthetic infusion pumps, paravertebral or transverse abdominis plane nerve blocks, long-acting local anesthetics, and botulinum toxins, have been shown to produce analgesic effects and decrease opioid use postoperatively. Combinations of non-opioid alternatives have been shown to be superior in the management of postoperative pain and opioid requirements. In 2008, Parsa demonstrated that gabapentin and celecoxib in combination preoperatively for subpectoral breast augmentation was significantly superior than celecoxib alone in reducing postoperative pain and opioid use [17]. Stephan and Parsa have extensive experience using non-opioid modalities of postoperative pain control, which has resulted in significant reduction in opioid administration postoperatively for patients undergoing various plastic surgery procedures [13].
\nSeveral other opioid reduction strategies in a surgical setting have been tested and shown to be effective in managing pain and decreasing opioid use. Preoperative patient education has shown to be effective in reducing the opioid requirement postoperatively. Sugai et al. demonstrated that preoperative oral and written education concerning the body’s response to pain reduced preoperative and postoperative opioid prescriptions [18]. When comparing patients that had opioid-free procedures to the patients receiving adjunct opioids, Parsa et al. found statistically significant reduction in time from end of operation to discharge, unplanned postoperative hospital admissions, and opioid use in the post-anesthesia care unit [19].
\nPain treatment and management has come a long way since ancient cultures. Several innovations during the nineteenth century made significant headway in opioid analgesics, and by the end of the twentieth century, hemodynamic stability during anesthesia was achievable through the application of opioids. However, in an era with significant opioid abuse, limiting opioid requirements in postoperative pain management is of greater importance. Opioids are associated with unwanted side effects, including nausea, vomiting, dizziness, constipation, and hyperalgesia. Not only are there several adverse effects with opioid use, including a high addictive potential, opioids also interfere with beta-endorphins, the human body’s potent natural analgesic. Opioid-free anesthesia provides a technique that can achieve intraoperative hemodynamic stability, immobility, and postoperative analgesia without opioids, and therefore, in the absence of the significant associated side effects. Judicious utilization of adjuvants like ketamine, gabapentinoids, intravenous lidocaine, magnesium sulfate, alpha-2 adrenoreceptor agonists, and beta-blockers contribute to enhanced recovery in specific patients with chronic pain and opioid dependence. Opioid-free anesthesia and other opioid-free pain relief strategies are essential in the control of the opioid crisis, are key in effective analgesia without unwanted opioid-related side effects, and are needed for postoperative recovery.
\nGlobal prevalence estimates suggest that approximately 196 million people lived with age-related macular degeneration (AMD) in 2020. Of these, 10.4 million people were living with moderate to severe vision impairment. In 2030, AMD is estimated to affect 243 million people due to aging [1]. The pathogenesis of AMD results from complex multifactorial interactions, including metabolic, genetic, and environmental [2]. AMD has been classified into two major subtypes: non-exudative or dry AMD and exudative or wet AMD. Although dry AMD represents 90% of patients, exudative AMD causes more severe loss of vision, being the target of most investigations [3]. These patients require very regular clinic visits, and the chronicity of anti-vascular endothelial growth factor (anti-VEGF) therapy can substantially impact the quality of life of the patient and the caregivers [4, 5]. This decrease can compromise anti-VEGF therapy compliance and explain the undertreatment of patients observed in real-world studies and the waiver of patients involved in clinical trials [6, 7]. New trials are focusing on improving the therapeutic options, particularly on the decrease of the associated burden. This chapter describes the current research on therapeutical approaches to treat the dry and exudative forms of AMD. Figure 1 summarizes the drugs and stages of development.
Summary of new drugs in the pipeline for the management of age-related macular degeneration (AMD).
The information was gathered from a medical literature review and ongoing clinical trials and their results in the area of AMD treatment using PubMed database (https://www.ncbi.nlm.nih.gov/pubmed). The words or medical head subjects used were: AMD and clinical trials. All relevant articles were imported into Zotero (Version 5.0, Center for History and New Media at Universidade George Mason, USA), and duplicate articles were deleted. We selected the promising therapies according to action mechanisms and excluded all therapies that had failed in clinical trials. Comments, editorials, and articles not written in English were not analyzed.
Although lampalizumab (anti-factor D Fab) and eculizumab (inhibitor of the activation of terminal complement) failed to slow geographic atrophy progression, the complement system has been implicated in the pathogenesis of geographic atrophy, and so, research on how to inhibit the complement system did not stop [8, 9].
Pegcetacoplan (APL-2; Apellis Pharmaceuticals, Waltham, Massachusetts, USA) is a synthetic molecule that selectively inhibits C3, effectively downregulating all three complement pathways. Phase 2 of the FILLY clinical trial compared patients receiving intravitreal injection (monthly and bi-monthly) with a control group. The results showed a 29% reduction in the rate of geographic atrophy and a better outcome in the monthly injection group. Moreover, it was observed that the risk of neovascular AMD was higher (18%) in the group subjected to monthly injections when comparing with the group subjected to bi-monthly injections (8%) and with the control group (1%) [10]. A phase 3 trial is currently in the recruitment phase (NCT03525600) [11].
Avacincaptad pegol (Zimura; Iveric Bio, New York, New York, USA) is a C5 inhibitor. Phase 2/3 GATHER1 clinical trial showed a significant reduction of geographic atrophy growth over 12 months, probably due to C3 activity preservation. A second confirmatory trial (GATHER2) is underway [12].
Retinal neuroprotection strategies have been studied for dry AMD, including apoptosis and necrosis prevention, and oxidative injury reduction [13].
Elamipretide (Stealth Biotherapeutics) is a mitochondria-targeted drug thought to reduce mitochondrial dysfunction. Phase 1 of the ReCLAIM clinical trial showed that elamipretide was safe, well-tolerated and that this drug may improve vision in patients with intermediate AMD, manifested as high-risk drusen [14]. Phase 2 ReCLAIM-2 clinical trial is underway [15].
Brimonidine tartrate (Allergan) is best known in glaucoma as the intraocular pressure (IOP) lowering agent. Phase 2A of the BEACON clinical trial assessed the intravitreally delivery of brimonidine through a delayed delivery system. Results showed a lower rate of geographic atrophy progression, although not statistically significant [16]. Phase 2B of the BEACON clinical trial demonstrated a reduction in geographic atrophy progression using higher doses of brimonidine [17]. Phase 3 of IMAGINE and ENVISION clinical trials are being designed [16].
One of the earliest changes in the retina that precede AMD symptoms is the formation of toxic vitamin A dimers.
ALK-001 (Alkeus Pharmaceuticals) is a chemically modified form of vitamin A that replaces the vitamin A in the body to prevent toxic vitamin A dimers. Studies demonstrated functional preservation of visual function in animal models [18]. Phase 3 of the SAGA clinical trial will measure the extent to which treatment with the oral capsule of ALK-001 slows geographic atrophy progression [19].
Cell therapy is an alternative strategy when the naturally existing cells are already too damaged to be preserved using neuroprotective agents. Human pluripotent stem cells (hPSCs) comprise human embryonic stem cells (hESCs) and human-induced pluripotent stem cells (hiPSCs). There are two subtypes of cell-based treatments: stem cell therapies that involve delivering new retinal pigment epithelial (RPE) cells to the subretinal space, and non-stem cell therapies based on cell implantation, which generates protective factors [20].
MA09-hRPE (Astellas Pharma) is hESC-derived Retinal Pigment Epithelium (hESC-RPE). The phases 1/2 clinical trial results confirmed that hESC-derived cells could serve as a potentially safe new source for regenerative medicine [21, 22, 23].
CPCB-RPE1 (The California Project to Cure Blindness-Retinal Pigment Epithelium1) is a polarized monolayer of hESC-RPE ultrathin, synthetic parylene substrate designed to mimic Bruch’s membrane. This therapy involves a subretinal implant. It was demonstrated the feasibility and safety of CPCB-RPE1 subretinal implantation in a comparable animal model [24]. Phase 1/2A of the clinical trial suggests that CPCB-RPE1 may improve visual function [25, 26].
Inflammation has been implicated in AMD pathogenesis and progression, even though it is no classical inflammatory disease like uveitis [27].
Doxycycline (Oracea; Galderma Laboratories, Fort Worth, Texas, USA) is an antibiotic that belongs to the tetracycline class of antibiotics and plays a role in immunomodulation, cell proliferation, angiogenesis, and the regulation of inflammation. Phase 3 of the TOGA clinical trial includes patients with geographic atrophy randomized in groups treated with Oracea® or placebo. The results are pending [28].
FHTR2163 (Genentech/Roche) is a new antibody delivered by intravitreal injection that inhibits the HTRA1 gene associated with geographic atrophy. Phase 2 of the GALLEGO clinical trial will evaluate the safety, tolerability, and efficacy of intravitreal injections of RG6147, administered every four or every eight weeks for a total of approximately 76 weeks, in participants with geographic atrophy secondary to AMD (when compared with the sham control) [29].
Potentially more durable anti-VEGF agents may reduce the burden of intravitreal injections, help stabilize the disease and improve compliance with treatment.
Brolucizumab (Beovu; Novartis, Basel, Switzerland) is the most recent intravitreal anti-VEGF agent to receive FDA approval. It is a humanized single-chain antibody fragment with a molecular weight of 26 kDa. Phase 3 of the HAWK and HARRIER clinical trials showed that brolucizumab was non-inferior to aflibercept regarding visual function as at week 48, more than 50% of the eyes treated with 6 mg of brolucizumab were maintained on q12w dosing intervals. Moreover, anatomic outcomes favored brolucizumab over aflibercept, and the overall safety results were similar between the two drugs [30].
Abicipar pegol (Allergan) is a novel class of molecules referred to as designed ankyrin repeat proteins (DARPin) that bind VEGF-A. DARPin is smaller and has a high affinity to VEGF, leading to greater stability and a longer-acting effect. The results of phase 3 of the SEQUOIA and CEDAR clinical trials showed that the eight and 12-week abicipar regimens were non-inferior to the ranibizumab’s monthly regimen, but patients had a much higher risk of developing intraocular inflammation (15% and 15.4% vs. 0%) [31, 32, 33]. The company modified the manufacturing process after finding impurities in the formulation, and subsequently, the MAPLE study showed a decrease in the incidence of intraocular inflammation to 8.9% [34]. A license for abicipar pegol was already submitted to the
Conbercept (Chengdu Kanghong Biotech Co., Ltd.) is an antibody that targets VEGF-A, VEGFB, VEGF-C, and placental growth factors. It was approved to treat exudative AMD in China in 2013. Phase 2 of the AURORA and phase 3 of the PHOENIX clinical trials showed the safety and efficacy of conbercept with three initial monthly treatments followed by quarterly treatments compared with the sham group [35, 36]. Phase 3 of the PANDA-1 and PANDA-2 global clinical trials compare maintenance doses of conbercept every 8 or 12 weeks with doses of aflibercept every eight weeks; results are expected in 2022 [37, 38].
OPT-302 (Opthea Limited) is a soluble form of the human VEGF receptor-3 (VEGFR-3), expressed as an Fc-fusion protein molecule design to inhibit VEGF-C and VEGF-D. Results from phases 1 and 2 of the ShORe and COAST clinical trials showed that this molecule was safer and had better visual outcomes than ranibizumab alone [39, 40]. Phase 3 of the ShORe and COAST clinical trials will be double-masked and sham-controlled. Treatment-naïve patients will be enrolled to assess the efficacy and safety of 2.0 mg OPT-302 combined with anti-VEGF-A therapy by comparison with anti-VEGF-A monotherapy (standard of care). Opthea expects to initiate patient recruitment in the first half of 2021 [41].
Faricimab (Roche, Genentech) is a novel bispecific antibody that targets both angiopoietin-2 (Ang-2) and VEGF-A. Phase 2 of the STAIRWAY clinical trial suggests that faricimab can be an effective maintenance therapy for exudative AMD with a dosing interval of 16 weeks [42, 43]. Phase 3 of the TANAYA and LUCERNE clinical trials will compare faricimab given every 16 weeks with aflibercept given every eight weeks [44, 45]. FDA requests for faricimab are expected to occur in 2021 for diabetic macular edema and in 2022 for exudative AMD.
KSI-301 (Kodiak Sciences) is a novel intravitreal, anti-VEGF antibody biopolymer conjugate designed to block all VEGF-A isoforms. Phase 1 of the DAZZLE clinical trial showed excellent safety, strong efficacy, and considerable durability in most patients for three or more months [46]. Phase 2 of the DAZZLE clinical trial is a prospective, randomized controlled clinical trial designed to evaluate the safety and efficacy of KSI-301 [47].
ONS-5010 (Outlook Therapeutics, Inc) is an ophthalmic formulation of bevacizumab. Phase 3 clinical trials compare monthly doses of ONS-5010 with a ranibizumab regimen of 3 monthly doses followed by quarterly doses [48]. FDA approval is expected in 2021 or 2022, and 12 years of exclusivity, protecting against bevacizumab biosimilars, are expected.
FYB201 (Formycon and Bioeq), SB11 (Samsung Bioepis), and Xlucane (Xbrane Biopharma) are biosimilars for ranibizumab under development that are expected to reach the market in less than one year when the patent for ranibizumab expires [49, 50, 51].
Aflibercept biosimilars are in phase 3 of clinical trials and are expected to reach the market between two and three years when the patent for aflibercept expires.
Although regorafenib, pazopanib, and LHA510 failed, other therapies showed promising results [52, 53, 54]. These formulations have the great advantage of being less invasive, but they can decrease the possibility of monitoring treatment compliance, as it happens with glaucoma patients medicated with lowering ocular hypertension drops.
PAN-90806 (PanOptica) is a topical formulation of a small molecule, a tyrosine kinase inhibitor (TKI), to treat wet AMD. In phase 1/2 of a dose-ranging clinical trial, more than half of patients receiving PAN-90806 once a day for 12 weeks completed the study without needing anti-VEGF rescue therapy. Fourteen of the 51 patients in the study, 88% experienced clinical improvement of their condition or their disease’s stability [55].
Squalamine lactate (Genaera Corporation) is an amino sterol derived from the dogfish shark’s cartilage that blocks VEGF, PDGF basic fibroblast growth binding calmodulin and its chaperones. A phase 2 clinical trial showed improved vision when squalamine lactate was used in combination with anti-VEGF treatments [56, 57].
The extended-release options may also reduce the burden of intravitreal injections.
The port delivery system (PDS; Hoffmann-La Roche) is a permanent, refillable implant, which is surgically placed at the pars plana through an incision in the sclera. PDS continuously releases concentrated ranibizumab by passive diffusion into the vitreous cavity.
Phase 2 of the LADDER clinical trial showed similar functional and anatomical outcomes after nine months of treatment with ranibizumab delivered through PDS or monthly intravitreal injections of ranibizumab [58, 59]. The mean time for the first PDS refill was 15 months, with 80% of patients not requiring a PDS refill for six or more months. Phase 3 of the ARCHWAY clinical trial is ongoing [60].
GB-102 (Graybug Vision) is a depot formulation of sunitinib malate that might need only 2 or 3 treatments per year [61]. Phase 2 of the ALTISSIMO clinical trial evaluated the safety and effect duration of GB-102 intravitreal injections administered every six months compared to aflibercept intravitreal injections administered every two months [62]. The results are currently pending.
NT-503 (Neurotech Pharmaceuticals) is a biological sustained drug delivery device that can provide anti-VEGF therapy’s continuous delivery. Preliminary studies show that the device can be implanted safely in humans [63]. The results of phases 1 and 2 of clinical trials are pending [64].
Aflibercept Hydrogel Depot (Regeneron Pharmaceuticals and Ocular Therapeutix™) is a delivery system based on a PolyActive hydrogel copolymer’s microparticles. In studies with animals intravitreally injected with aflibercept hydrogel depot a, sustained and controlled release of aflibercept was achieved. No adverse effects in the eyes of healthy rhesus macaques were observed for up to 6 months [65].
pSivida Durasert Technology (EyePoint Pharmaceuticals, Inc.) can be used to deliver different drugs for extended periods (months or even years) with a single application. Delivery of a tyrosine kinase inhibitor in animals provided promising results [66].
Gene therapy is based on the insertion of an anti-VEGF coding sequence into retinal cells’ DNA through a viral vector.
ADVM-022 (Adverum) produces an anti-VEGF-A fusion protein delivered through intravitreal injection via the AAV.7 m8 viral vector. Phase 1 of the OPTIC clinical trial showed that treatment with a single injection prevented additional anti-VEGF treatment over six months [67, 68].
RGX-314 (RegenexBio) (Rockville, MA, USA) produces an anti-VEGF A fab delivered through a subretinal treatment via an AAV8 viral vector. Phases 1/2a of the AAVIATE clinical trial showed a decrease in injection burden without significant inflammation or adverse effects [69]. Phase 2b of the AAVIATE clinical trial will explore a suprachoroidal injection [70].
Retinostat (Oxford BioMedica) is a lentiviral vector expressing endostatin and angiostatin to inhibit angiogenesis potentially. Phase 1 clinical trial showed that the LentiVector® gene therapy platform safely and efficiently delivered genes to the retina resulting in stable, long-term expression [71].
AAV2-sFLT01 (Genzyme, a Sanofi Company) is a vector that expresses a modified soluble Flt1 receptor designed to neutralize the proangiogenic activities of VEGF via an intravitreal injection. Phase 1 clinical trial showed that AAV2-sFLT01 was safe and that there was good tolerance to this vector [72]. After three years of follow-up, AAV2-sFLT01 appears to be generally safe, well-tolerated and does not appear to raise any new safety concerns [73].
AAVCAGsCD59 (Hemera Biosciences) is a molecule that targets the terminal step of complement activation that leads to the formation of the membrane attack complex. Two-phase 1 clinical trials for both exudative and dry AMD showed that subretinal injection of AAV-CD59 attenuated the formation of laser-induced choroidal neovascularization by around 60% in mice, even when the site of delivery was distal to the laser-induced choroidal neovascularization site [74].
An alternative for genetic interference is small interfering RNA (siRNA) that inhibits the protein-coding genes and prevent protein synthesis. Delivery can be by the topical installation or intravitreal injection. Bevasiranib (Opko) was the first siRNA used, but it did not show efficacy in phase 3 of the COBALT clinical trial [75]. AGN211745 (Alergan) was designed to reduce pathologic angiogenesis mediated by both VEGF
PF-655 (Pfizer) is a siRNA that inhibits expression of the hypoxia-inducible gene RTP801, which inhibits the mammalian target of the rapamycin (mTOR) signaling pathway and reduces VEGF-A production. Results from phase 2 of the MONET clinical trial showed that the combination of PF-655 with ranibizumab led to an average gain in visual acuity superior to the one observed for patients under ranibizumab monotherapy [77].
There are many potential therapeutic options for AMD. New treatment options for dry AMD that slow disease progression or re-establish retinal cells are becoming a reality. For wet AMD, new drugs that could lead to a longer half-life in the vitreous, lower costs, and more potent anti-angiogenesis activity, should be approved soon. With the increase of population longevity, AMD incidence and prevalence will most probably increase, and these therapies may reduce both the societal and individual treatment burden. Although they are in the earlier clinical trial phases, the authors consider that the cell-based therapies for dry AMD and gene therapy for wet AMD are the more promising therapies for the future because they tend to correct the source’s problem. The new COVID vaccines also represent a significant step in this area, and these novel technologies may be future treatments for many other diseases.
The authors declare no conflict of interest.
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\n\nLast updated: 2020-11-27
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Shohel"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},subject:{topic:{id:"1411",title:"Oenology",slug:"oenology",parent:{id:"1410",title:"Viticulture",slug:"agricultural-and-biological-sciences-viticulture"},numberOfBooks:2,numberOfSeries:0,numberOfAuthorsAndEditors:122,numberOfWosCitations:95,numberOfCrossrefCitations:64,numberOfDimensionsCitations:136,videoUrl:null,fallbackUrl:null,description:null},booksByTopicFilter:{topicId:"1411",sort:"-publishedDate",limit:12,offset:0},booksByTopicCollection:[{type:"book",id:"8054",title:"Advances in Grape and Wine Biotechnology",subtitle:null,isOpenForSubmission:!1,hash:"f6b9b3b3d887ed9e7c0ad09cb07edf2b",slug:"advances-in-grape-and-wine-biotechnology",bookSignature:"Antonio Morata and Iris Loira",coverURL:"https://cdn.intechopen.com/books/images_new/8054.jpg",editedByType:"Edited by",editors:[{id:"180952",title:"Prof.",name:"Antonio",middleName:null,surname:"Morata",slug:"antonio-morata",fullName:"Antonio Morata"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6077",title:"Grapes and Wines",subtitle:"Advances in Production, Processing, Analysis and Valorization",isOpenForSubmission:!1,hash:"61fe601d66e441800c8ed9503f86280f",slug:"grapes-and-wines-advances-in-production-processing-analysis-and-valorization",bookSignature:"António Manuel Jordão and Fernanda Cosme",coverURL:"https://cdn.intechopen.com/books/images_new/6077.jpg",editedByType:"Edited by",editors:[{id:"186821",title:"Prof.",name:"António",middleName:null,surname:"M. Jordão",slug:"antonio-m.-jordao",fullName:"António M. Jordão"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],booksByTopicTotal:2,seriesByTopicCollection:[],seriesByTopicTotal:0,mostCitedChapters:[{id:"58633",doi:"10.5772/intechopen.72800",title:"The Evolution of Polyphenols from Grapes to Wines",slug:"the-evolution-of-polyphenols-from-grapes-to-wines",totalDownloads:2029,totalCrossrefCites:5,totalDimensionsCites:13,abstract:"Polyphenols play an important role in the quality of wines, due to their contribution to the wine sensory properties: color, astringency and bitterness. They act as antioxidants, having positive role in human health. They can be divided into non-flavonoid (hydroxybenzoic and hydroxycinnamic acids and stilbenes) and flavonoid compounds (anthocyanins, flavan-3-ols and flavonols). Anthocyanins are responsible for the color of red grapes and wines, hydroxycinnamic and hydroxybenzoic acids act as copigments, stilbenes as antioxidants and the flavan-3-ols are mainly responsible for the astringency, bitterness and structure of wines, being involved also in the color stabilization during aging. This chapter will focus on the chemical structures of the main polyphenols, their identification and quantification in grapes and wines by advanced analytical techniques, highlighting also the maceration and aging impact on the polyphenols evolution. The factors influencing the phenolic accumulation in grapes are also reviewed, emphasizing as well the relationship between phenolic content in grapes versus wine. Polyphenolic changes during the wine making process are highlighted along with the main polyphenol extraction methods and analysis techniques. This research will contribute to the improvement in the knowledge of polyphenols: their presence in grapes, the relationship with wine quality and the influence of the external factors on their evolution.",book:{id:"6077",slug:"grapes-and-wines-advances-in-production-processing-analysis-and-valorization",title:"Grapes and Wines",fullTitle:"Grapes and Wines - Advances in Production, Processing, Analysis and Valorization"},signatures:"Violeta-Carolina Niculescu, Nadia Paun and Roxana-Elena Ionete",authors:[{id:"187102",title:"Dr.",name:"Roxana",middleName:null,surname:"Ionete",slug:"roxana-ionete",fullName:"Roxana Ionete"},{id:"206056",title:"Dr.",name:"Violeta",middleName:"Carolina",surname:"Niculescu",slug:"violeta-niculescu",fullName:"Violeta Niculescu"},{id:"207020",title:"Mrs.",name:"Nadia",middleName:null,surname:"Paun",slug:"nadia-paun",fullName:"Nadia Paun"}]},{id:"58638",doi:"10.5772/intechopen.72823",title:"Occurrence and Analysis of Sulfur Compounds in Wine",slug:"occurrence-and-analysis-of-sulfur-compounds-in-wine",totalDownloads:1957,totalCrossrefCites:4,totalDimensionsCites:11,abstract:"Sulfur compounds play an important role in the sensory characteristics of wine. These molecules can derive from the grape, in which the non-volatile forms are usually present as glycosylated molecules, the metabolic activities of yeast and bacteria, the chemical reactions taking place during the wine aging and storage, and the environment. The sulfur compounds include molecules positively correlated to the aromatic profile of wine, namely the volatile thiols, and are responsible for certain defects, imparting notes described as cabbage, onion, rotten egg, garlic, sulfur and rubber. Due to the low concentration of these molecules in wine, their high reactivity and the matrix complexity, the analytical methods which enable their detection and quantification represent a challenge. The solid phase microextraction (SPME) technique has been developed for sulfur compounds associated with off-flavors. The analysis of volatile thiols usually requires a derivatization followed by gas chromatography (GC)-MS or UPLC-MS methods. Besides the sulfur-containing aromas, another sulfur compound that deserves mention is the reduced glutathione (GSH) which has been widely studied due to its antioxidant properties. The analysis of GSH has been proposed using a liquid chromatography technique (HPLC or UPLC) coupled with fluorescence, MS and UV detectors.",book:{id:"6077",slug:"grapes-and-wines-advances-in-production-processing-analysis-and-valorization",title:"Grapes and Wines",fullTitle:"Grapes and Wines - Advances in Production, Processing, Analysis and Valorization"},signatures:"Daniela Fracassetti and Ileana Vigentini",authors:[{id:"207271",title:"Dr.",name:"Daniela",middleName:null,surname:"Fracassetti",slug:"daniela-fracassetti",fullName:"Daniela Fracassetti"},{id:"220967",title:"Dr.",name:"Ileana",middleName:null,surname:"Vigentini",slug:"ileana-vigentini",fullName:"Ileana Vigentini"}]},{id:"66619",doi:"10.5772/intechopen.85692",title:"Contribution of the Microbiome as a Tool for Estimating Wine’s Fermentation Output and Authentication",slug:"contribution-of-the-microbiome-as-a-tool-for-estimating-wine-s-fermentation-output-and-authenticatio",totalDownloads:1095,totalCrossrefCites:5,totalDimensionsCites:9,abstract:"Wine is the alcoholic beverage which is the product of alcoholic fermentation, usually, of fresh grape must. Grape microbiome is the source of a vastly diverse pool of filamentous fungi, yeast, and bacteria, the combination of which plays a crucial role for the quality of the final product of any grape must fermentation. In recent times, the significance of this pool of microorganisms has been acknowledged by several studies analyzing the microbial ecology of grape berries of different geographical origins, cultural practices, grape varieties, and climatic conditions. Furthermore, the microbial evolution of must during fermentation process has been overstudied. The combination of the microbial evolution along with metabolic and sensorial characterizations of the produced wines could lead to the suggestion of the microbial terroir. These aspects are today leading to open a new horizon for products such as wines, especially in the case of PDO-PGI products. The aims of this review is to describe (a) how the microbiome communities are dynamically differentiated during the process of fermentation from grape to ready-to-drink wine, in order to finalize each wine’s unique sensorial characteristics, and (b) whether the microbiome could be used as a fingerprinting tool for geographical indication, based on high-throughput sequencing (HTS) technologies. Nowadays, it has been strongly indicated that microbiome analysis of grapes and fermenting musts using next-generation sequencing (NGS) could open a new horizon for wine, in the case of protected designation of origin (PDO) and protected geographical indication (PGI) determination.",book:{id:"8054",slug:"advances-in-grape-and-wine-biotechnology",title:"Advances in Grape and Wine Biotechnology",fullTitle:"Advances in Grape and Wine Biotechnology"},signatures:"Dimitrios A. Anagnostopoulos, Eleni Kamilari and Dimitrios Tsaltas",authors:[{id:"180885",title:"Associate Prof.",name:"Dimitris",middleName:null,surname:"Tsaltas",slug:"dimitris-tsaltas",fullName:"Dimitris Tsaltas"},{id:"203761",title:"MSc.",name:"Dimitris",middleName:null,surname:"Anagnostopoulos",slug:"dimitris-anagnostopoulos",fullName:"Dimitris Anagnostopoulos"},{id:"271801",title:"Ms.",name:"Elena",middleName:null,surname:"Kamilari",slug:"elena-kamilari",fullName:"Elena Kamilari"}]},{id:"67444",doi:"10.5772/intechopen.86443",title:"Somatic Variation and Cultivar Innovation in Grapevine",slug:"somatic-variation-and-cultivar-innovation-in-grapevine",totalDownloads:1036,totalCrossrefCites:4,totalDimensionsCites:9,abstract:"Paradoxically, continuous vegetative multiplication of traditional grapevine cultivars aimed to maintain cultivar attributes in this highly heterozygous species ends in the accumulation of considerable somatic variation. This variation has long contributed to cultivar adaptation and evolution under changing environmental and cultivation conditions and has also been a source of novel traits. Understanding how this somatic variation originates provides tools for genetics-assisted tracking of selected variants and breeding. Potentially, the identification of the mutations causing the observed phenotypic variation can now help to direct genome editing approaches to improve the genotype of elite traditional cultivars. Molecular characterization of somatic variants can also generate basic information helping to understand gene biological function. In this chapter, we review the state of the art on somatic variation in grapevine at phenotypic and genome sequence levels, present possible strategies for the study of this variation, and describe a few examples in which the genetic and molecular basis or very relevant grapevine traits were successfully identified.",book:{id:"8054",slug:"advances-in-grape-and-wine-biotechnology",title:"Advances in Grape and Wine Biotechnology",fullTitle:"Advances in Grape and Wine Biotechnology"},signatures:"Pablo Carbonell-Bejerano, Carolina Royo, Nuria Mauri, Javier Ibáñez and José Miguel Martínez Zapater",authors:[{id:"287215",title:"Prof.",name:"Jose Miguel",middleName:null,surname:"Martinez Zapater",slug:"jose-miguel-martinez-zapater",fullName:"Jose Miguel Martinez Zapater"},{id:"287226",title:"Dr.",name:"Javier",middleName:null,surname:"Ibáñez",slug:"javier-ibanez",fullName:"Javier Ibáñez"},{id:"300441",title:"Dr.",name:"Pablo",middleName:null,surname:"Carbonell-Bejerano",slug:"pablo-carbonell-bejerano",fullName:"Pablo Carbonell-Bejerano"},{id:"300442",title:"Dr.",name:"Carolina",middleName:null,surname:"Royo",slug:"carolina-royo",fullName:"Carolina Royo"},{id:"300444",title:"Dr.",name:"Nuria",middleName:null,surname:"Mauri",slug:"nuria-mauri",fullName:"Nuria Mauri"}]},{id:"67833",doi:"10.5772/intechopen.87042",title:"Effects of Vine Water Status on Yield Components, Vegetative Response and Must and Wine Composition",slug:"effects-of-vine-water-status-on-yield-components-vegetative-response-and-must-and-wine-composition",totalDownloads:1125,totalCrossrefCites:5,totalDimensionsCites:8,abstract:"Despite Vitis vinifera L. is a drought-tolerant species—rainfed traditionally grown in a very diversity of climates—irrigation has more and more become a usual practice aimed to obtain regular yields along seasons and to control must composition. Results on vineyard irrigation are dependent on the timing, length and intensity of the water deficit. From budbreak to flowering, shoot growth is very sensitive to water stress, while reproductive growth is almost unaffected. Severe water deficit during fruit set can reduce yield by affecting ovary cell multiplication and expansion. During maturation water stress induces yield reduction by limiting berry growth; along this phase must composition is also affected. There is a positive, linear relationship between must sugar content and available water; however, no relationship has been found to either total acidity or pH. Biosynthesis of anthocyanins and fruity aromas is enhanced by water deficit. Usually, wines from moderate irrigation treatments scored the highest. There is a general agreement that severe, long water deficits diminish must quality, leaf area, fertility and yield, and it has a negative carryover effect on the next seasons by limiting wood reserves to be used the following seasons.",book:{id:"8054",slug:"advances-in-grape-and-wine-biotechnology",title:"Advances in Grape and Wine Biotechnology",fullTitle:"Advances in Grape and Wine Biotechnology"},signatures:"Pilar Baeza, Pedro Junquera, Emilio Peiro, José Ramón Lissarrague, David Uriarte and Mar Vilanova",authors:[{id:"222515",title:"Dr.",name:"David",middleName:null,surname:"Uriarte",slug:"david-uriarte",fullName:"David Uriarte"},{id:"285912",title:"Dr.Ing.",name:"Pilar",middleName:null,surname:"Baeza",slug:"pilar-baeza",fullName:"Pilar Baeza"},{id:"285917",title:"Dr.",name:"Mar",middleName:null,surname:"Vilanova",slug:"mar-vilanova",fullName:"Mar Vilanova"},{id:"285919",title:"Dr.",name:"Pedro",middleName:null,surname:"Junquera",slug:"pedro-junquera",fullName:"Pedro Junquera"},{id:"285922",title:"Dr.",name:"Jose Ramón",middleName:null,surname:"Lissarrague",slug:"jose-ramon-lissarrague",fullName:"Jose Ramón Lissarrague"}]}],mostDownloadedChaptersLast30Days:[{id:"58638",title:"Occurrence and Analysis of Sulfur Compounds in Wine",slug:"occurrence-and-analysis-of-sulfur-compounds-in-wine",totalDownloads:1957,totalCrossrefCites:4,totalDimensionsCites:11,abstract:"Sulfur compounds play an important role in the sensory characteristics of wine. These molecules can derive from the grape, in which the non-volatile forms are usually present as glycosylated molecules, the metabolic activities of yeast and bacteria, the chemical reactions taking place during the wine aging and storage, and the environment. The sulfur compounds include molecules positively correlated to the aromatic profile of wine, namely the volatile thiols, and are responsible for certain defects, imparting notes described as cabbage, onion, rotten egg, garlic, sulfur and rubber. Due to the low concentration of these molecules in wine, their high reactivity and the matrix complexity, the analytical methods which enable their detection and quantification represent a challenge. The solid phase microextraction (SPME) technique has been developed for sulfur compounds associated with off-flavors. The analysis of volatile thiols usually requires a derivatization followed by gas chromatography (GC)-MS or UPLC-MS methods. Besides the sulfur-containing aromas, another sulfur compound that deserves mention is the reduced glutathione (GSH) which has been widely studied due to its antioxidant properties. The analysis of GSH has been proposed using a liquid chromatography technique (HPLC or UPLC) coupled with fluorescence, MS and UV detectors.",book:{id:"6077",slug:"grapes-and-wines-advances-in-production-processing-analysis-and-valorization",title:"Grapes and Wines",fullTitle:"Grapes and Wines - Advances in Production, Processing, Analysis and Valorization"},signatures:"Daniela Fracassetti and Ileana Vigentini",authors:[{id:"207271",title:"Dr.",name:"Daniela",middleName:null,surname:"Fracassetti",slug:"daniela-fracassetti",fullName:"Daniela Fracassetti"},{id:"220967",title:"Dr.",name:"Ileana",middleName:null,surname:"Vigentini",slug:"ileana-vigentini",fullName:"Ileana Vigentini"}]},{id:"57497",title:"Recovering Ancient Grapevine Varieties: From Genetic Variability to In Vitro Conservation, A Case Study",slug:"recovering-ancient-grapevine-varieties-from-genetic-variability-to-in-vitro-conservation-a-case-stud",totalDownloads:1776,totalCrossrefCites:2,totalDimensionsCites:5,abstract:"A great number of varieties have been described in grapevine; however, few of them are currently in use. The increasing concern on varietal diversity loss has encouraged actions for recovering and preserving grapevine germplasm, which represents valuable resources for breeding as well as for diversification in grapevine-derived products. On the other hand, it is expected that this important crop, which is distributed in warm areas worldwide, will suffer the climate changes. Therefore, it is also convenient the identification of intravarietal variability and the recovery of accessions well adapted to particular environments. In this chapter, we will contribute to highlight the importance of recovering ancient materials, the usefulness of SSR markers to determine their molecular profile, the importance to analyze their virus status, and the possibilities that offer biotechnological tools for virus sanitation and in vitro storage as a complement of field preservation. In this context, we have evaluated different grapevine accessions and developed in vitro culture protocols for micropropagation, sanitation, and storage grapevine cultivars. In this work, we report the results obtained for the historic variety “Valencí Blanc” (or “Beba”) and the historic and endangered variety “Esclafagerres” (“Esclafacherres” or “Esclafacherris”).",book:{id:"6077",slug:"grapes-and-wines-advances-in-production-processing-analysis-and-valorization",title:"Grapes and Wines",fullTitle:"Grapes and Wines - Advances in Production, Processing, Analysis and Valorization"},signatures:"Carmina Gisbert, Rosa Peiró, Tania San Pedro, Antonio Olmos,\nCarles Jiménez and Julio García",authors:[{id:"207745",title:"Dr.",name:"Carmina",middleName:null,surname:"Gisbert",slug:"carmina-gisbert",fullName:"Carmina Gisbert"},{id:"207748",title:"Dr.",name:"Rosa María",middleName:null,surname:"Peiró",slug:"rosa-maria-peiro",fullName:"Rosa María Peiró"},{id:"207749",title:"Ms.",name:"Tania",middleName:null,surname:"San Pedro Galán",slug:"tania-san-pedro-galan",fullName:"Tania San Pedro Galán"},{id:"207750",title:"Dr.",name:"Antonio",middleName:null,surname:"Olmos",slug:"antonio-olmos",fullName:"Antonio Olmos"}]},{id:"58633",title:"The Evolution of Polyphenols from Grapes to Wines",slug:"the-evolution-of-polyphenols-from-grapes-to-wines",totalDownloads:2029,totalCrossrefCites:5,totalDimensionsCites:13,abstract:"Polyphenols play an important role in the quality of wines, due to their contribution to the wine sensory properties: color, astringency and bitterness. They act as antioxidants, having positive role in human health. They can be divided into non-flavonoid (hydroxybenzoic and hydroxycinnamic acids and stilbenes) and flavonoid compounds (anthocyanins, flavan-3-ols and flavonols). Anthocyanins are responsible for the color of red grapes and wines, hydroxycinnamic and hydroxybenzoic acids act as copigments, stilbenes as antioxidants and the flavan-3-ols are mainly responsible for the astringency, bitterness and structure of wines, being involved also in the color stabilization during aging. This chapter will focus on the chemical structures of the main polyphenols, their identification and quantification in grapes and wines by advanced analytical techniques, highlighting also the maceration and aging impact on the polyphenols evolution. The factors influencing the phenolic accumulation in grapes are also reviewed, emphasizing as well the relationship between phenolic content in grapes versus wine. Polyphenolic changes during the wine making process are highlighted along with the main polyphenol extraction methods and analysis techniques. This research will contribute to the improvement in the knowledge of polyphenols: their presence in grapes, the relationship with wine quality and the influence of the external factors on their evolution.",book:{id:"6077",slug:"grapes-and-wines-advances-in-production-processing-analysis-and-valorization",title:"Grapes and Wines",fullTitle:"Grapes and Wines - Advances in Production, Processing, Analysis and Valorization"},signatures:"Violeta-Carolina Niculescu, Nadia Paun and Roxana-Elena Ionete",authors:[{id:"187102",title:"Dr.",name:"Roxana",middleName:null,surname:"Ionete",slug:"roxana-ionete",fullName:"Roxana Ionete"},{id:"206056",title:"Dr.",name:"Violeta",middleName:"Carolina",surname:"Niculescu",slug:"violeta-niculescu",fullName:"Violeta Niculescu"},{id:"207020",title:"Mrs.",name:"Nadia",middleName:null,surname:"Paun",slug:"nadia-paun",fullName:"Nadia Paun"}]},{id:"67760",title:"Production and Marketing of Low-Alcohol Wine",slug:"production-and-marketing-of-low-alcohol-wine",totalDownloads:1302,totalCrossrefCites:3,totalDimensionsCites:6,abstract:"Moderate wine consumption may be associated with specific health benefits and a healthy lifestyle. However, increased amounts of ethanol are cytotoxic and associated with adverse health outcomes. Alcohol reduction in wine might be an avenue to reduce alcohol related harm without forcing consumers to compromise on lifestyle and benefit from positive aspects of moderate consumption. The aim of this review is to give an overview of viticultural and pre and post fermentation methods to produce low-alcohol wine, and to summarize the current evidence on the consumer acceptance and behaviour related to low-alcohol wine. Strategies for the labelling and marketing of wines with reduced alcohol content are discussed.",book:{id:"8054",slug:"advances-in-grape-and-wine-biotechnology",title:"Advances in Grape and Wine Biotechnology",fullTitle:"Advances in Grape and Wine Biotechnology"},signatures:"Tamara Bucher, Kristine Deroover and Creina Stockley",authors:[{id:"289140",title:"Dr.",name:"Creina",middleName:null,surname:"Stockley",slug:"creina-stockley",fullName:"Creina Stockley"},{id:"289141",title:"Dr.",name:"Tamara",middleName:null,surname:"Bucher",slug:"tamara-bucher",fullName:"Tamara Bucher"},{id:"289142",title:"Ms.",name:"Kristine",middleName:null,surname:"Deroover",slug:"kristine-deroover",fullName:"Kristine Deroover"}]},{id:"57946",title:"Microbiological, Physical, and Chemical Procedures to Elaborate High-Quality SO2-Free Wines",slug:"microbiological-physical-and-chemical-procedures-to-elaborate-high-quality-so2-free-wines",totalDownloads:1617,totalCrossrefCites:5,totalDimensionsCites:8,abstract:"Sulfur dioxide (SO2) is the most preservative used in the wine industry and has been widely applied, as antioxidant and antibacterial agent. However, the use of sulfur dioxide implicates a range of adverse clinical effects. Therefore, the replacement of the SO2 content in wines is one of the most important challenges for scientist and winemakers. This book chapter gives an overview regarding different microbiological, physical, and chemical alternatives to elaborate high-quality SO2-free wines. In the present chapter, original research articles as well as review articles and results obtained by the research group of the Wine Technology Center (VITEC) are shown. This study provides useful information related to this novel and healthy type of wines, highlighting the development of winemaking strategies and procedures.",book:{id:"6077",slug:"grapes-and-wines-advances-in-production-processing-analysis-and-valorization",title:"Grapes and Wines",fullTitle:"Grapes and Wines - Advances in Production, Processing, Analysis and Valorization"},signatures:"Raúl Ferrer-Gallego, Miquel Puxeu, Laura Martín, Enric Nart, Claudio\nHidalgo and Imma Andorrà",authors:[{id:"207221",title:"Dr.",name:"Raúl",middleName:null,surname:"Ferrer-Gallego",slug:"raul-ferrer-gallego",fullName:"Raúl Ferrer-Gallego"},{id:"208597",title:"Dr.",name:"Miquel",middleName:null,surname:"Puxeu",slug:"miquel-puxeu",fullName:"Miquel Puxeu"},{id:"208598",title:"Dr.",name:"Laura",middleName:null,surname:"Martín",slug:"laura-martin",fullName:"Laura Martín"},{id:"208599",title:"Mr.",name:"Enric",middleName:null,surname:"Nart",slug:"enric-nart",fullName:"Enric Nart"},{id:"208600",title:"Dr.",name:"Claudio",middleName:null,surname:"Hidalgo",slug:"claudio-hidalgo",fullName:"Claudio Hidalgo"},{id:"208601",title:"Dr.",name:"Imma",middleName:null,surname:"Andorrà",slug:"imma-andorra",fullName:"Imma Andorrà"}]}],onlineFirstChaptersFilter:{topicId:"1411",limit:6,offset:0},onlineFirstChaptersCollection:[{id:"81659",title:"State-of-the-Art Knowledge about 2,4,6-Trichloroanisole (TCA) and Strategies to Avoid Cork Taint in Wine",slug:"state-of-the-art-knowledge-about-2-4-6-trichloroanisole-tca-and-strategies-to-avoid-cork-taint-in-wi",totalDownloads:28,totalDimensionsCites:0,doi:"10.5772/intechopen.103709",abstract:"Cork stoppers have been used for many centuries to seal wine in various vessels. Therefore, corks have become a traditional part of wine packaging in many countries and still play an important role for the entire wine industry. Nowadays, there is a wide option of bottle cork stoppers on the market, such as natural corks, agglomerated and technical stoppers (1 + 1), etc. These cork closures have a number of advantages, including positive sustainable and ecological aspects. Natural cork material can also be responsible for cork taint, which imparts musty/moldy or wet cardboard off-odors to the wine. However, corks are not the only source of cork taint in wine, as will be shown in the present chapter. Over the past decades, a number of compounds have been detected that can contribute to the cork taint. Among them, haloanisoles play a major role, in particular 2,4,6-trichloroanisole (TCA), which has been shown to be responsible for 50–80% or more of musty defect cases in wine. Currently, the cork and wine industries have developed a number of tools and technologies to effectively prevent cork tait in wine or to remove it if the wine is already contaminated. These practical as well as analytical questions about the TCA defects are the subject of the actual chapter.",book:{id:"10901",title:"Grapes and Wine",coverURL:"https://cdn.intechopen.com/books/images_new/10901.jpg"},signatures:"Andrii Tarasov, Miguel Cabral, Christophe Loisel, Paulo Lopes, Christoph Schuessler and Rainer Jung"},{id:"78620",title:"Table Grapes: There Is More to Vitiviniculture than Wine…",slug:"table-grapes-there-is-more-to-vitiviniculture-than-wine",totalDownloads:142,totalDimensionsCites:0,doi:"10.5772/intechopen.99986",abstract:"Table grapes are fruits intended for fresh human consumption due to their sensory attributes and nutritional value. The objective of this chapter is to review the existing knowledge about table grapes, including a description of different varieties, with particular emphasis on the new highly appreciated seedless varieties. Following an introductory note on the world distribution and production of table grapes, also considering the impact of climate change, selected varieties of table grapes will be characterized in terms of their physiology, postharvest features, and consumer preferences. A morphological description of each variety, with emphasis on grape skin, grape rachis and grape cluster will be included. A final note on the drying of table grapes into raisins, and the most appropriate varieties for drying, will be given. The major changes occurring throughout the growth, development, and ripening phases of table grapes production will be discussed, regarding both physical (skin color and skin and pulp texture) and chemical (phenolic compounds, sugar content and acidity) parameters, as well as growth regulators.",book:{id:"10901",title:"Grapes and Wine",coverURL:"https://cdn.intechopen.com/books/images_new/10901.jpg"},signatures:"Ana Cristina Agulheiro-Santos, Marta Laranjo and Sara Ricardo-Rodrigues"},{id:"79500",title:"New Insights about the Influence of Yeasts Autolysis on Sparkling Wines Composition and Quality",slug:"new-insights-about-the-influence-of-yeasts-autolysis-on-sparkling-wines-composition-and-quality",totalDownloads:96,totalDimensionsCites:0,doi:"10.5772/intechopen.101314",abstract:"Sparkling wines elaborated using the traditional method undergo a second fermentation in the bottle. This process involves an aging time in contact with the lees, which enriches the wine in various substances, especially proteins, mannoproteins and polysaccharides, thanks to the autolysis of the yeasts. As a result of this yeast autolysis, sparkling wines benefit from better integration of carbon dioxide and a clear sensory improvement, especially in the case of long aging. This chapter synthetizes the main results that our research group has obtained about the influence of yeasts autolysis on sparkling wines composition and quality during last years, making special emphasis on the capacity of the lees to release proteins and polysaccharides as well as on their capacity to consume oxygen and thus protect the sparkling wines from oxidation.",book:{id:"10901",title:"Grapes and Wine",coverURL:"https://cdn.intechopen.com/books/images_new/10901.jpg"},signatures:"Pere Pons-Mercadé, Pol Giménez, Glòria Vilomara, Marta Conde, Antoni Cantos, Nicolas Rozès, Sergi Ferrer, Joan Miquel Canals and Fernando Zamora"},{id:"79110",title:"Microbial Decontamination by Pulsed Electric Fields (PEF) in Winemaking",slug:"microbial-decontamination-by-pulsed-electric-fields-pef-in-winemaking",totalDownloads:83,totalDimensionsCites:0,doi:"10.5772/intechopen.101112",abstract:"Pulsed Electric Fields (PEF) is a non-thermal technique that causes electroporation of cell membranes by applying very short pulses (μs) of a high-intensity electric field (kV/cm). Irreversible electroporation leads to the formation of permanent conductive channels in the cytoplasmic membrane of cells, resulting in the loss of cell viability. This effect is achieved with low energy requirements and minimal deterioration of quality. This chapter reviews the studies hitherto conducted to evaluate the potential of PEF as a technology for microbial decontamination in the winemaking process for reducing or replacing the use of SO2, for guaranteeing reproducible fermentations or for wine stabilization.",book:{id:"10901",title:"Grapes and Wine",coverURL:"https://cdn.intechopen.com/books/images_new/10901.jpg"},signatures:"Carlota Delso, Alejandro Berzosa, Jorge Sanz, Ignacio Álvarez and Javier Raso"},{id:"78993",title:"pH Control and Aroma Improvement Using the Non-Saccharomyces Lachancea thermotolerans and Hanseniaspora spp. Yeasts to Improve Wine Freshness in Warm Areas",slug:"ph-control-and-aroma-improvement-using-the-non-saccharomyces-lachancea-thermotolerans-and-hanseniasp",totalDownloads:90,totalDimensionsCites:0,doi:"10.5772/intechopen.100538",abstract:"Lachancea thermotolerans is a yeast species that works as a powerful bio tool capable of metabolizing grape sugars into lactic acid via lactate dehydrogenase enzymes. The enological impact is an increase in total acidity and a decrease in pH levels (sometimes >0.5 pH units) with a concomitant slight reduction in alcohol (0.2–0.4% vol.), which helps balance freshness in wines from warm areas. In addition, higher levels of molecular SO2 are favored, which helps to decrease SO2 total content and achieve better antioxidant and antimicrobial performance. The simultaneous use with some apiculate yeast species of the genus Hanseniaspora helps to improve the aromatic profile through the production of acetyl esters and, in some cases, terpenes, which makes the wine aroma more complex, enhancing floral and fruity scents and making more complex and fresh wines. Furthermore, many species of Hanseniaspora increase the structure of wines, thus improving their body and palatability. Ternary fermentations with Lachancea thermotolerans and Hanseniaspora spp. sequentially followed by Saccharomyces cerevisiae are a useful bio tool for producing fresher wines from neutral varieties in warm areas.",book:{id:"10901",title:"Grapes and Wine",coverURL:"https://cdn.intechopen.com/books/images_new/10901.jpg"},signatures:"Antonio Morata, Carlos Escott, Iris Loira, Juan Manuel Del Fresno, Cristian Vaquero, María Antonia Bañuelos, Felipe Palomero, Carmen López and Carmen González"},{id:"78970",title:"Alternatives to CU Applications in Viticulture. How R&D Projects Can Provide Applied Solutions, Helping to Establish Legislation Limits",slug:"alternatives-to-cu-applications-in-viticulture-how-r-d-projects-can-provide-applied-solutions-helpin",totalDownloads:182,totalDimensionsCites:2,doi:"10.5772/intechopen.100500",abstract:"Copper (Cu) and its based preparations have been used for over 200 years to control fungi and bacterial diseases in cultivated plants. Downy mildew caused by the obligate biotrophic oomycete Plasmopara viticola is one of the most relevant and recurrent diseases of grapevines. Recently, the use of Cu is being limited by some regulations because of its high impact at different levels (health and environmental problems). Due to its accumulation in soil, this metal causes a little controversy with the principles of sustainable production. Therefore, international legislation and initiatives have recently been arisen to start limiting its use, with the main goal to replace it. In this framework, some alternatives have been tested and others are recently being developed to replace, at least partially, the use of Cu in viticulture. Many of them, are being developed and tested under the scope of research and development EU funded projects. To not compromise sustainability targets in viticulture, results from these R&D projects need to be considered to assess the present risks of using Cu in viticulture and to better support establishing limits for its applications, considering soils vulnerability, while no sustainable alternatives are available in the market.",book:{id:"10901",title:"Grapes and Wine",coverURL:"https://cdn.intechopen.com/books/images_new/10901.jpg"},signatures:"Mario De La Fuente, David Fernández-Calviño, Bartosz Tylkowski, Josep M. Montornes, Magdalena Olkiewicz, Ruth Pereira, Anabela Cachada, Tito Caffi, Giorgia Fedele and Felicidad De Herralde"}],onlineFirstChaptersTotal:16},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:0,limit:8,total:null},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:87,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:98,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:27,numberOfPublishedChapters:288,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:9,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:11,numberOfPublishedChapters:139,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:8,numberOfPublishedChapters:129,numberOfOpenTopics:0,numberOfUpcomingTopics:2,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!1},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:107,numberOfOpenTopics:3,numberOfUpcomingTopics:1,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:10,numberOfPublishedChapters:103,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:12,numberOfOpenTopics:2,numberOfUpcomingTopics:1,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:0,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!1},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:0,numberOfPublishedChapters:11,numberOfOpenTopics:4,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{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"}}}},{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. 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Ongoing issues, recent advances, and future diagnostic approaches and therapeutic strategies will also be discussed. This book series will focus on various aspects and properties of infectious diseases whose deep understanding is essential for safeguarding the human race from losing resources and economies due to pathogens.",coverUrl:"https://cdn.intechopen.com/series/covers/6.jpg",latestPublicationDate:"May 19th, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:13,editor:{id:"131400",title:"Prof.",name:"Alfonso J.",middleName:null,surname:"Rodriguez-Morales",slug:"alfonso-j.-rodriguez-morales",fullName:"Alfonso J. Rodriguez-Morales",profilePictureURL:"https://mts.intechopen.com/storage/users/131400/images/system/131400.png",biography:"Dr. Rodriguez-Morales is an expert in tropical and emerging diseases, particularly zoonotic and vector-borne diseases (especially arboviral diseases). He is the president of the Travel Medicine Committee of the Pan-American Infectious Diseases Association (API), as well as the president of the Colombian Association of Infectious Diseases (ACIN). He is a member of the Committee on Tropical Medicine, Zoonoses, and Travel Medicine of ACIN. He is a vice-president of the Latin American Society for Travel Medicine (SLAMVI) and a Member of the Council of the International Society for Infectious Diseases (ISID). Since 2014, he has been recognized as a Senior Researcher, at the Ministry of Science of Colombia. He is a professor at the Faculty of Medicine of the Fundacion Universitaria Autonoma de las Americas, in Pereira, Risaralda, Colombia. He is an External Professor, Master in Research on Tropical Medicine and International Health, Universitat de Barcelona, Spain. He is also a professor at the Master in Clinical Epidemiology and Biostatistics, Universidad Científica del Sur, Lima, Peru. In 2021 he has been awarded the “Raul Isturiz Award” Medal of the API. Also, in 2021, he was awarded with the “Jose Felix Patiño” Asclepius Staff Medal of the Colombian Medical College, due to his scientific contributions to COVID-19 during the pandemic. He is currently the Editor in Chief of the journal Travel Medicine and Infectious Diseases. His Scopus H index is 47 (Google Scholar H index, 68).",institutionString:"Institución Universitaria Visión de las Américas, Colombia",institution:null},editorTwo:null,editorThree:null},subseries:{paginationCount:5,paginationItems:[{id:"91",title:"Sustainable Economy and Fair Society",coverUrl:"https://cdn.intechopen.com/series_topics/covers/91.jpg",isOpenForSubmission:!0,annualVolume:11975,editor:{id:"181603",title:"Dr.",name:"Antonella",middleName:null,surname:"Petrillo",slug:"antonella-petrillo",fullName:"Antonella Petrillo",profilePictureURL:"https://mts.intechopen.com/storage/users/181603/images/system/181603.jpg",biography:"Antonella Petrillo is a Professor at the Department of Engineering of the University of Naples “Parthenope”, Italy. She received her Ph.D. in Mechanical Engineering from the University of Cassino. Her research interests include multi-criteria decision analysis, industrial plant, logistics, manufacturing and safety. She serves as an Associate Editor for the International Journal of the Analytic Hierarchy Process. She is a member of AHP Academy and a member of several editorial boards. 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Her focus is on quality, innovation, leadership, and personalised learning. She works primarily at the strategic and policy levels, both nationally and internationally, and with key international organisations. She is committed to promoting and improving OFDL in the context of SDG4 and the future of education. Ossiannilsson has more than 20 years of experience in her current field, but more than 40 years in the education sector. She works as a reviewer and expert for the European Commission and collaborates with the Joint Research Centre for Quality in Open Education. Ossiannilsson also collaborates with ITCILO and ICoBC (International Council on Badges and Credentials). She is a member of the ICDE Board of Directors and has previously served on the boards of EDEN and EUCEN. Ossiannilsson is a quality expert and reviewer for ICDE, EDEN and the EADTU. She chairs the ICDE OER Advocacy Committee and is a member of the ICDE Quality Network. 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She is a member of the Digital Skills and Jobs Coalition Sweden and Vice President of the Swedish Association for Distance Education. She is currently working on a government initiative on quality in distance education at the National Council for Higher Education. 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