More than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
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Our breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
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“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
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Additionally, each book published by IntechOpen contains original content and research findings.
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We are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
Simba Information has released its Open Access Book Publishing 2020 - 2024 report and has again identified IntechOpen as the world’s largest Open Access book publisher by title count.
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Simba Information is a leading provider for market intelligence and forecasts in the media and publishing industry. The report, published every year, provides an overview and financial outlook for the global professional e-book publishing market.
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IntechOpen, De Gruyter, and Frontiers are the largest OA book publishers by title count, with IntechOpen coming in at first place with 5,101 OA books published, a good 1,782 titles ahead of the nearest competitor.
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Since the first Open Access Book Publishing report published in 2016, IntechOpen has held the top stop each year.
\n\n\n\n
More than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\n\n
Our breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\n\n
“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\n\n
Additionally, each book published by IntechOpen contains original content and research findings.
\n\n
We are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
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\n'}],latestNews:[{slug:"intechopen-supports-asapbio-s-new-initiative-publish-your-reviews-20220729",title:"IntechOpen Supports ASAPbio’s New Initiative Publish Your Reviews"},{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"}]},book:{item:{type:"book",id:"10313",leadTitle:null,fullTitle:"Reproductive Hormones",title:"Reproductive Hormones",subtitle:null,reviewType:"peer-reviewed",abstract:"Reproductive Hormones examines the pathophysiology of reproductive hormones on the human body. The breadth of the book’s content is extensive, covering the effects of sex steroids on multiple organ systems. New information is presented in a clear, concise fashion and material is clinically relevant to practicing providers in endocrinology and other specialties.",isbn:"978-1-83962-230-4",printIsbn:"978-1-83962-229-8",pdfIsbn:"978-1-83962-287-8",doi:"10.5772/intechopen.91499",price:119,priceEur:129,priceUsd:155,slug:"reproductive-hormones",numberOfPages:218,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"b5c9effb4087b6f7d6276cc236f00a28",bookSignature:"Courtney Marsh",publishedDate:"May 5th 2021",coverURL:"https://cdn.intechopen.com/books/images_new/10313.jpg",numberOfDownloads:3965,numberOfWosCitations:2,numberOfCrossrefCitations:4,numberOfCrossrefCitationsByBook:0,numberOfDimensionsCitations:8,numberOfDimensionsCitationsByBook:0,hasAltmetrics:1,numberOfTotalCitations:14,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"June 4th 2020",dateEndSecondStepPublish:"September 11th 2020",dateEndThirdStepPublish:"November 10th 2020",dateEndFourthStepPublish:"January 29th 2021",dateEndFifthStepPublish:"March 30th 2021",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"255491",title:"Dr.",name:"Courtney",middleName:null,surname:"Marsh",slug:"courtney-marsh",fullName:"Courtney Marsh",profilePictureURL:"https://mts.intechopen.com/storage/users/255491/images/system/255491.jpg",biography:"After graduating from the University of Kansas School of Medicine (KUMC), Dr. Marsh went on to complete her obstetrics and gynecology residency at Emory University, Atlanta, Georgia. For fellowship, Dr. Marsh trained in reproductive endocrinology and infertility at the University of Michigan.\n\nAs a fellow, she researched hypothalamic feedback of estrogen as related to the pubertal onset and menstrual cyclicity. She also completed research using neuroimaging techniques to better understand polycystic ovary syndrome (PCOS). She has several publications in the scientific literature and is also a member of many medical associations.\n\n Dr. Marsh specializes in treating women with infertility and PCOS. She is proud to provide both medical and surgical options in treating infertility including assisted reproductive technology.",institutionString:"University of Kansas Medical Center",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"2",totalChapterViews:"0",totalEditedBooks:"2",institution:{name:"University of Kansas Medical Center",institutionURL:null,country:{name:"United States of America"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"1014",title:"Reproductive Endocrinology and Infertility",slug:"medicine-endocrinology-reproductive-endocrinology-and-infertility"}],chapters:[{id:"75047",title:"Role of Sex Hormones in Human Body",doi:"10.5772/intechopen.95778",slug:"role-of-sex-hormones-in-human-body",totalDownloads:601,totalCrossrefCites:0,totalDimensionsCites:1,hasAltmetrics:1,abstract:"Gonadal Steroids hormones play an important role in the reproductive and non-reproductive systems. Estrogen has important rule in cardiovascular system as it has vasodilator effect and reduces or prevents platelet activation. In addition, it improves the profile of circulating lipoproteins. All of which may explain why women at premenopausal age are less likely to have heart disease than menopause women or men. E2 play a grate effect on the skeletal system as it is one of the strongest regulators of osteoblast and osteoclast function, and it is responsible for the reduction of adipose tissue and regulation of the body weight, and also has dermatological effect,hence it stimulates the proliferation of keratinocytes and prevents their apoptosis, in addition to the progesterone which increases collagen synthesis. Estrogen is necessary for the functioning and integrity of the tissues of the urinary system specially of the lower urinary tract. Sex steroid are crucial for nervous system, as progesterone is important for production of neurosteroid, and estrogen is currently used in Parkinson’s and Alzheimer’s disease because of its effects on mental health. The androgens also have a crucial biological effects on neural, muscle, bone, adipose tissue,prostate, cardiovascular, haemopoietic, and the reproductive systems. The gonadal steroid hormones play an important role in immune system and regulating the immune response against different viral or bacterial infections.",signatures:"Nassrin Malik Aubead",downloadPdfUrl:"/chapter/pdf-download/75047",previewPdfUrl:"/chapter/pdf-preview/75047",authors:[{id:"329956",title:"Dr.",name:"Nassrin",surname:"Malik Aubead",slug:"nassrin-malik-aubead",fullName:"Nassrin Malik Aubead"}],corrections:null},{id:"75025",title:"Nociceptive TRP Channels and Sex Steroids",doi:"10.5772/intechopen.95552",slug:"nociceptive-trp-channels-and-sex-steroids",totalDownloads:307,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Proteins belonging to Transient Receptor Potential (TRP) family are nonselective cation channels that play an essential role in mammalian physiology, functioning as transducers of several environmental signals including those of chemical, thermal and mechanical natures. A subgroup of these receptors is expressed in sensory neurons where they are activated by noxious stimuli and are key players of pain responses in the organism. Some TRP channels are molecular targets for the classical and non-classical effects of sex steroids. This chapter will describe the close relationship between nociceptive TRP channels and sex steroids as well as their impact on nociception and pain-related responses.",signatures:"Óscar Enciso-Pablo, Karina Angélica Méndez-Reséndiz, Tamara Rosenbaum and Sara Luz Morales-Lázaro",downloadPdfUrl:"/chapter/pdf-download/75025",previewPdfUrl:"/chapter/pdf-preview/75025",authors:[{id:"334008",title:"Associate Prof.",name:"Sara Luz",surname:"Morales-Lázaro",slug:"sara-luz-morales-lazaro",fullName:"Sara Luz Morales-Lázaro"},{id:"344471",title:"BSc.",name:"Óscar",surname:"Enciso-Pablo",slug:"oscar-enciso-pablo",fullName:"Óscar Enciso-Pablo"},{id:"344472",title:"MSc.",name:"Karina Angélica",surname:"Méndez-Reséndiz",slug:"karina-angelica-mendez-resendiz",fullName:"Karina Angélica Méndez-Reséndiz"},{id:"344473",title:"Dr.",name:"Tamara",surname:"Rosenbaum",slug:"tamara-rosenbaum",fullName:"Tamara Rosenbaum"}],corrections:null},{id:"75942",title:"Androgens’ Effects across the Lifespan in Men and Animal Models",doi:"10.5772/intechopen.96707",slug:"androgens-effects-across-the-lifespan-in-men-and-animal-models",totalDownloads:326,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"The clinical literature and recent studies in our laboratory using rodent models demonstrate that there are individual differences in androgens’ pleiotropic effects across the lifespan that need to be better understood. The question to address that challenges the field is that levels of androgens (current and/or prior) may not drive differing responses to androgens. The clinical example of Post-finasteride Syndrome, in which side-effects persist long after treatment is discontinued, supports investigations of this novel question relating to long-term effects of androgen manipulations, independent of existing levels of androgens.",signatures:"Cheryl A. Frye, Jennifer K. Torgersen, Vincent F. Lembo and Kelly Drew",downloadPdfUrl:"/chapter/pdf-download/75942",previewPdfUrl:"/chapter/pdf-preview/75942",authors:[{id:"104839",title:"Dr.",name:"Kelly",surname:"Drew",slug:"kelly-drew",fullName:"Kelly Drew"},{id:"324395",title:"Prof.",name:"Cheryl A.",surname:"Frye",slug:"cheryl-a.-frye",fullName:"Cheryl A. Frye"},{id:"324396",title:"Mr.",name:"Vincent F.",surname:"Lembo",slug:"vincent-f.-lembo",fullName:"Vincent F. Lembo"},{id:"345686",title:"Dr.",name:"Jennifer K.",surname:"Torgerson",slug:"jennifer-k.-torgerson",fullName:"Jennifer K. Torgerson"}],corrections:null},{id:"73546",title:"Androgen Signaling in the Placenta",doi:"10.5772/intechopen.94007",slug:"androgen-signaling-in-the-placenta",totalDownloads:432,totalCrossrefCites:0,totalDimensionsCites:1,hasAltmetrics:0,abstract:"The placenta is a multifunctional, transitory organ that mediates transport of nutrients and waste, gas exchange, and endocrine signaling. In fact, placental secretion of hormones is critical for maintenance of pregnancy, as well as growth and development of healthy offspring. In this chapter, the role of androgens in placental development and function is highlighted. First, a brief summary will be provided on the different mammalian placental types followed by an overview of placental steroidogenesis. Next, the chapter will focus on genomic and non-genomic androgen signaling pathways. Finally, an overview will be provided on the current status of androgen signaling in the placenta during normal and abnormal pregnancies.",signatures:"Agata M. Parsons Aubone, River Evans and Gerrit J. Bouma",downloadPdfUrl:"/chapter/pdf-download/73546",previewPdfUrl:"/chapter/pdf-preview/73546",authors:[{id:"276521",title:"Ph.D.",name:"Gerrit J.",surname:"Bouma",slug:"gerrit-j.-bouma",fullName:"Gerrit J. Bouma"},{id:"325864",title:"Dr.",name:"Agata M.",surname:"Parsons",slug:"agata-m.-parsons",fullName:"Agata M. Parsons"},{id:"325865",title:"Ms.",name:"River",surname:"Evans",slug:"river-evans",fullName:"River Evans"}],corrections:null},{id:"73469",title:"Testosterone",doi:"10.5772/intechopen.94017",slug:"testosterone",totalDownloads:378,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Testosterone is a hormone produced majorly by the testicles in adult human _ men. The hormone affects a man’s appearance and sexual development, stimulates sperm production and regulates a man’s sex drive. It also helps build muscles and bone mass. Testosterone production decreases with age. Its production is at its highest in a man’s early adulthood and drops slowly each year afterwards. The normal range of testosterone in the body is typically 300 to 1000 ng/dL for men and 15 to 70 ng/dL for women. A range of symptoms can occur if its production drastically drops below normal. Men with low T can experience a range of symptoms if its decrease becomes significant. Low testosterone, or low T, is diagnosed when levels fall below 300 ng/dL. A blood test, called ‘a serum testosterone test’, is used to determine the level of circulating testosterone. When the body does not produce the right amount of testosterone, the condition is called hypogonadism. This is sometimes called “low T”. Men diagnosed with hypogonadism can benefit from testosterone therapy. However, therapy is not usually recommended, unless testosterone level falls quite below the normal range for age. This is because there are some natural remedies which can help.",signatures:"Kizito Omona",downloadPdfUrl:"/chapter/pdf-download/73469",previewPdfUrl:"/chapter/pdf-preview/73469",authors:[{id:"329364",title:"Dr.",name:"Kizito",surname:"Omona",slug:"kizito-omona",fullName:"Kizito Omona"}],corrections:null},{id:"75080",title:"Androgens and Cardiovascular Risk Factors in Polycystic Ovary Syndrome",doi:"10.5772/intechopen.96005",slug:"androgens-and-cardiovascular-risk-factors-in-polycystic-ovary-syndrome",totalDownloads:305,totalCrossrefCites:0,totalDimensionsCites:1,hasAltmetrics:1,abstract:"Polycystic Ovary Syndrome (PCOS) is the most common endocrine disorder in reproductive-aged women. Clinical or biochemical signs of androgen excess is a cardinal feature of the syndrome and are present in approximately 80% of women with PCOS. Increased blood pressure and insulin resistance, two major cardiovascular risk factors, are frequently present in women with PCOS. This chapter aims to highlight the fundamental role of androgens in mediating the increased blood pressure and insulin resistance in women with PCOS. This chapter is also a call for action to develop new pharmacological therapies that target the androgen synthesis and androgen receptor activation dysregulation present in women with PCOS. These novel therapies will allow to prevent or mitigate the excess androgen-mediated cardiovascular risk factors that affect women with PCOS.",signatures:"Licy L. Yanes Cardozo, Alexandra M. Huffman, Jacob E. Pruett and Damian G. Romero",downloadPdfUrl:"/chapter/pdf-download/75080",previewPdfUrl:"/chapter/pdf-preview/75080",authors:[{id:"329590",title:"Dr.",name:"Licy",surname:"Yanes Cardozo",slug:"licy-yanes-cardozo",fullName:"Licy Yanes Cardozo"},{id:"341598",title:"Dr.",name:"Damian G.",surname:"Romero",slug:"damian-g.-romero",fullName:"Damian G. Romero"},{id:"345475",title:"MSc.",name:"Alexandra M.",surname:"Huffman",slug:"alexandra-m.-huffman",fullName:"Alexandra M. Huffman"},{id:"345476",title:"BSc.",name:"Jacob E.",surname:"Pruett",slug:"jacob-e.-pruett",fullName:"Jacob E. Pruett"}],corrections:null},{id:"74462",title:"Serum Sex Hormone Profiles in Potentially Resectable Esophageal Cancer",doi:"10.5772/intechopen.95030",slug:"serum-sex-hormone-profiles-in-potentially-resectable-esophageal-cancer",totalDownloads:232,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Esophageal cancer (EC) affects men far more commonly than women. Numerous epidemiological studies have suggested that the hormonal milieu may play a role in this gender bias. However, there is little known about circulating sex hormone levels in relation to the risk of EC development. In this chapter, the correlation between circulating sex hormone levels and mRNA expression of estrogen receptors (ER) in normal esophageal mucosal samples and EC biopsies from patients with potentially resectable EC is studied. Moreover, the association of serum sex hormones levels with and clinico-pathological features of EC is analysed.",signatures:"Waleed Al-Khyatt and Syed Yusuf Iftikhar",downloadPdfUrl:"/chapter/pdf-download/74462",previewPdfUrl:"/chapter/pdf-preview/74462",authors:[{id:"324810",title:"Dr.",name:"Waleed",surname:"Al-Khyatt",slug:"waleed-al-khyatt",fullName:"Waleed Al-Khyatt"},{id:"325036",title:"Dr.",name:"Syed Yusef",surname:"Iftikhar",slug:"syed-yusef-iftikhar",fullName:"Syed Yusef Iftikhar"}],corrections:null},{id:"73669",title:"Small Molecules Inhibit Extranuclear Signaling by Estrogen: A Promising Strategy to Halt Breast Cancer Progression and Metastasis",doi:"10.5772/intechopen.94052",slug:"small-molecules-inhibit-extranuclear-signaling-by-estrogen-a-promising-strategy-to-halt-breast-cance",totalDownloads:358,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"The sex hormone estrogen plays critical roles in reproductive and sexual development. It regulates the expression and activity of key signaling molecules critical in various cellular signaling pathways. These signals are mediated by its binding to estrogen receptors alpha (ERα) and beta (ERβ). ERα has been shown to greatly participate in extranuclear signaling, inducing tumorogenesis and breast cancer metastasis. Small molecules from plants are reported with better selectivity toward tumorigenic cells with negligible toxicity when compared to their synthetic counterpart. The molecules used in this study were first probed for their drug-likeness and their pharmacokinetic profile was elucidated before docking them to the ligand binding domain of the human ERα followed by a post docking prime analysis. All tested molecules had good drug-like and pharmacokinetic properties when compared to about 95% of orally available drugs as predicted by qikprop. The docking results revealed a strong binding interaction with ERα, influenced mostly by the vicinal diol groups of the studied molecules. These resulted in a conformational change, inducing receptor dimerization and altering the interactions of the sex hormone with other proteins. The studied ligands are promising in strongly inhibiting the binding of estrogen to ERα, thus limiting its extranuclear signaling.",signatures:"Imaobong Etti, Chukwuemeka Nwafor and Grace Essien",downloadPdfUrl:"/chapter/pdf-download/73669",previewPdfUrl:"/chapter/pdf-preview/73669",authors:[{id:"218775",title:"Dr.",name:"Imaobong",surname:"Etti",slug:"imaobong-etti",fullName:"Imaobong Etti"},{id:"329431",title:"Dr.",name:"Chukwuemeka",surname:"Nwafor",slug:"chukwuemeka-nwafor",fullName:"Chukwuemeka Nwafor"},{id:"329432",title:"Dr.",name:"Grace",surname:"Essien",slug:"grace-essien",fullName:"Grace Essien"}],corrections:null},{id:"74544",title:"Non-Reproductive Effects of Estradiol: Hydromineral Homeostasis Control",doi:"10.5772/intechopen.95348",slug:"non-reproductive-effects-of-estradiol-hydromineral-homeostasis-control",totalDownloads:286,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"The hydromineral homeostasis is fundamental to survival due to maintenance constant the osmotic properties of the plasma and proper tissue perfusion pressure, being maintained primarily through the regulation of the ingestion and urinary excretion of water and electrolytes, mainly sodium. The Renin-Angiotensin System (RAS) plays an essential role in the maintenance of hydromineral homeostasis by eliciting sodium and water intake and by inducing sodium urinary retention through aldosterone release and hemodynamic effect via angiotensin II a key component of the RAS. The hypothalamus-pituitary system also plays a fundamental role in the maintenance of body fluid homeostasis by secreting vasopressin (AVP) and oxytocin (OT) in response to osmotic and non-osmotic, and volemic stimuli. Furthermore, some studies report that besides reproductive function and sexual behavior, ovarian gonadal hormones, mainly 17β-estradiol (E2), modulate other non-reproductive functions such as cardiovascular system, body fluid balance, mood, mental state, memory, and cognition. Estradiol is known to mediate hydromineral homeostasis and blood pressure mainly by attenuating RAS actions. On the other hand, estradiol modulates neurohypophysial hormones secretion in many different ways. In this chapter, we will discuss the main non-reproductive effects of E2 on the control of hydromineral homeostasis, focusing on ingestive behavior and neurohypophyseal hormonal release.",signatures:"Gislaine Almeida-Pereira, Lucila L.K. Elias and José Antunes-Rodrigues",downloadPdfUrl:"/chapter/pdf-download/74544",previewPdfUrl:"/chapter/pdf-preview/74544",authors:[{id:"150400",title:"Dr.",name:"Lucila L.K.",surname:"Elias",slug:"lucila-l.k.-elias",fullName:"Lucila L.K. Elias"},{id:"329530",title:"Dr.",name:"Gislaine",surname:"Almeida-Pereira",slug:"gislaine-almeida-pereira",fullName:"Gislaine Almeida-Pereira"},{id:"339189",title:"Dr.",name:"José",surname:"Antunes-Rodrigues",slug:"jose-antunes-rodrigues",fullName:"José Antunes-Rodrigues"}],corrections:null},{id:"74165",title:"Kisspeptin: Role in Female Infertility",doi:"10.5772/intechopen.94925",slug:"kisspeptin-role-in-female-infertility",totalDownloads:397,totalCrossrefCites:4,totalDimensionsCites:5,hasAltmetrics:0,abstract:"Kisspeptin is a neuropeptide encoded by the kisspeptin gene (Kiss1) and located in different brain regions, primarily in the hypothalamus. Kisspeptin and its receptor G-protein-coupled receptor-54 (GPR54), are also found in behavioural brain regions such as the hippocampus and cortex. Kisspeptin, a very powerful neuropeptide that stimulates the secretion of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the pituitary, does this by increasing gonadotropin-releasing hormone (GnRH) levels. In recent studies, it has been noted that kisspeptin is effective on reproductive functions. Globally 8 to 12% of couples have infertility problems, and the majority are residents of developing countries. Approximately 70% of infertility cases are caused by fertility problems in women. The frequency of infertility in women continues to increase every year and the underlying factors require further research. Bearing this problem in mind, this review examines the possible role of kisspeptin in female infertility. In doing so, it aims to find out how future application of kisspeptin may potentially unravel the neural reproductive disorder.",signatures:"Abdulsamed Kükürt, Mushap Kuru, Ömer Faruk Başer and Mahmut Karapehlivan",downloadPdfUrl:"/chapter/pdf-download/74165",previewPdfUrl:"/chapter/pdf-preview/74165",authors:[{id:"218960",title:"Dr.",name:"Mushap",surname:"Kuru",slug:"mushap-kuru",fullName:"Mushap Kuru"},{id:"219081",title:"Dr.",name:"Abdulsamed",surname:"Kükürt",slug:"abdulsamed-kukurt",fullName:"Abdulsamed Kükürt"},{id:"325646",title:"MSc.",name:"Ömer Faruk",surname:"Başer",slug:"omer-faruk-baser",fullName:"Ömer Faruk Başer"},{id:"458012",title:"Dr.",name:"Mahmut",surname:"Karapehlivan",slug:"mahmut-karapehlivan",fullName:"Mahmut Karapehlivan"}],corrections:null},{id:"74803",title:"Neuroendocrinology of Pregnancy: Participation of Sex Hormones",doi:"10.5772/intechopen.95774",slug:"neuroendocrinology-of-pregnancy-participation-of-sex-hormones",totalDownloads:344,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Pregnancy is characterized by hormonal changes, critical for the mother’s physiological adaptation, exercising a role in the fetus’s development, maintenance, protection, and nutrition. Since born, the neuroendocrine system’s involvement is necessary to prevent the embryo from being rejected by the mother’s immune system. These changes are regulated by fluctuations in hormones such as Progesterone, Testosterone, Androstenedione, Dehydroepiandrosterone, Estradiol, Prolactin, human Placental Lactogen, human Chorionic Gonadotropin, and Thyroid hormones, which promote the mother’s development and the fetus (maternal-fetal development). Therefore, given the great importance of these hormones during pregnancy, this chapter will explain the preclinical and clinical participation of sex hormones in maternal-fetal development.",signatures:"Luz Irene Pascual Mathey",downloadPdfUrl:"/chapter/pdf-download/74803",previewPdfUrl:"/chapter/pdf-preview/74803",authors:[{id:"325220",title:"Ph.D.",name:"Luz Irene",surname:"Pascual Mathey",slug:"luz-irene-pascual-mathey",fullName:"Luz Irene Pascual Mathey"}],corrections:null}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},subseries:null,tags:null},relatedBooks:[{type:"book",id:"9785",title:"Endometriosis",subtitle:null,isOpenForSubmission:!1,hash:"f457ca61f29cf7e8bc191732c50bb0ce",slug:"endometriosis",bookSignature:"Courtney Marsh",coverURL:"https://cdn.intechopen.com/books/images_new/9785.jpg",editedByType:"Edited by",editors:[{id:"255491",title:"Dr.",name:"Courtney",surname:"Marsh",slug:"courtney-marsh",fullName:"Courtney Marsh"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"805",title:"Sex Steroids",subtitle:null,isOpenForSubmission:!1,hash:"69b8296a72c662d5d96bf61a1b394eda",slug:"sex-steroids",bookSignature:"Scott M. 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\n\t\t\t
1. Introduction
\n\t\t\t
Vertebrate retina has routinely been isolated from bovine [1-4] or rat eyes [5]. However, many animal models for disturbances in neuronal signalling rely on gene inactivation or transgenes in mice. To get access to the isolated retina from these model systems to investigate neuronal processing, the technique of retina isolation and recording in a closed chamber was transferred from the bovine to the murine eye.
\n\t\t\t
The ERG recordings of the isolated and superfused retina from bovine eye were most successfully performed in a closed recording chamber, in which a defined and controlled oxygen concentration can be achieved. Under these conditions, repetitive ERG recordings (interval time 5 min) can be performed up to 10 hours [4]. For rat and murine ERG recordings an open system was introduced recently, in which oxygen may escape easier, and stable recordings were shortened to about 90 min [6]. Therefore, we tried to optimize murine ERG recordings in the same closed system as it was introduced for frog and bovine retina [7;8].
\n\t\t
\n\t\t
\n\t\t\t
2. Optimization of murine ERG recordings and applications
\n\t\t\t
In the first section the history to optimize murine ERG recordings will be described for the last six years, in which initially an incomplete ERG was recorded, which was mainly dominated by the a-wave. After changes for the retina isolation as well as for the recording conditions, a full ERG was obtained, which even could be subdivided for the b-wave response into at least two different fractions [9].
\n\t\t\t
Finally, two important topics will be covered for successful ERG recordings.
\n\t\t\t
Using still the bovine retina, it will be analysed that a trace metal free solution can be achieved by using a tricine-based buffer system, which chelates heavy metal divalent cations selectively. Such a buffering may be very helpful for ERG recordings in the presence of submicromolar copper ion concentrations, which may be as important as investigations with the artificial Ni2+-ions [3;10] or the native occurring Zn2+-ions [11].
Flashes of high light intensity will be used to trigger repetitive ERG responses and to test the stability of the optimized murine ERG recording conditions.
\n\t\t\t
\n\t\t\t\t
2.1. Development of methods to record full murine ERGs for basal and reciprocal signalling
\n\t\t\t\t
The diameter of a murine eye (male, 10 – 15 weeks of age) is about 10-fold smaller than the diameter of the bovine eye (age of 9 – 12 month). Therefore, an optimal isolation procedure is critical for subsequent successful and stable ERG recordings from the isolated murine retina.
\n\t\t\t\t
In the following three chapters, we introduce three different procedures, which were used in our laboratory to realize and to improve the reproducible ERG recording from the murine retina.
\n\t\t\t\t
The first procedure, the retina isolation by a rotating razor blade, was used to mimic the way of working as done with the bovine retina. Instead of using a knife to open up the eye bulb, we added a razor blade to a rotator, which cut the murine eye bulb laying in the stator very harsh, as we noted later. Under these conditions, the ERG recordings were dominated by the a-wave.
\n\t\t\t\t
The second and the third procedure used a more gentle way to open up the eye bulb. The access to the retina was achieved by opening up the eye bulb at the level of the cornea. Consecutively, the lens was removed, and the eye cup was gently cut apart. The second and the third procedure differ with respect to the waiting time, after which ERG recordings were started. Initially (second procedure), we realized that a full ERG was better achieved by incubating the retina in nutrient solution for four hours in darkness. One may assume that it recovered from the ischemic conditions during the isolation procedure. Although basic signalling recovered during these 4 hours, reciprocal signalling obviously vanished. Therefore, we omitted preincubation, and started immediately (third procedure).
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The main focus of our research was directed to understand the mechanisms of reciprocal signalling via voltage-gated Ca2+ channels, sensitive to heavy metal cations (Ni2+, Zn2+, Cu2+). It was started first by using NiCl2, an often used non-selective Ca2+-channel blocker with some preference for Cav2.3/R-type and for Cav3.2/T-type Ca2+ channels, which have IC50 values at 10 µM. Therefore, an optimal recording of only basal retinal signal transduction was not sufficient, and we had to pay attention to more favourable conditions for ERG recording, preserving also signalling via feedback from amacrine cells to bipolar neurons.
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2.1.1. Retina isolation by a rotating razor blade
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Initial preparations of the murine retina followed the idea that the eye bulb should be opened up in a similar way as for the bovine retina by cutting the eye bulb at the ora serrata region. Therefore, a rotating razor blade was used, which led fast and reproducibly to a nearly full sized retina, isolated from the proximal cup of the remaining eye bulb. Under these conditions, it was possible to record photoreceptor responses reliably for at least 90 min [12]. Interestingly, from the incomplete ERG, which was characterized by a large a-wave (Fig. 1A – 1C), the photoreceptor response was sensitive towards low concentrations of dihydropyridines (25 nM racemic isradipine). Under similar recording conditions, the bovine photoreceptor response was insensitive even towards 2 µM isradipine [12].
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Detailed analysis of the mechanism for dihydropyridine sensitivity of the murine photoreceptor response (a-wave) led to the detection that preincubation of the murine retina in 1 – 10 mM D-aspartate, a well known antagonist of transsynaptic signalling [13], eliminated the sensitivity towards this classical L-type Ca2+ channel antagonist. Similarly, also the sensitivity of the a-wave towards the T-type Ca2+ channel antagonist mibefradil (1 - 10 µM) was reversibly occluded by D-aspartate preincubation leading to the conclusion that minor transsynaptic signal transduction was present before aspartate application [12]. Such a very minor b-wave component could be deduced from our recordings by subtracting the mean values of murine ERGs in the presence of aspartate (1 mM) from those ERGs initially recorded before applying aspartate (Fig. 1D).
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Figure 1.
Murine ERGs from isolated retinas of “razor-blade” isolated retina. The retina was dark-adapted and the electroretinogram was elicited by a single white flash at intervals of 3 min. The flash intensity was initially set to 6.3 lx (Fig. 1 and procedure 1) at the retinal surface using calibrated neutral density filters with light stimulation lasting 500 ms (see bar under the ERG traces), controlled by a timer operating a mechanical shutter system. Later (procedure 2 and 3) the flash intensity was raised to 63 mlx. During all conditions, the ERG was recorded by using two silver/silver-chloride electrodes, which are on both sides of the recording chamber. The ERG was amplified and bandpass limited between 1 and 300 Hz. The signal was AD converted and stored using a PC-based signal acquisition and analysis system. Temperature was 30°C (procedure 1), and 27.5°C (procedure 2 and 3). Flow rate for nutrient solution (Sickel solution) was 1 ml/min (procedure 1), and 2 ml/min (procedure 2 and 3). A. ERG recorded 6 min after begin of superfusion of nutrient solution. B. ERG recorded 90 min after begin of superfusion of nutrient solution. C. Superposition of traces from panel A. and B. The dashed line represents the ERG trace after 90 min of superfusion. Panel A. – C. represents data from the same experiment. D. ERG traces before (open circles) and after superfusion of 1 mM D-aspartate for 30 min (filled circles). The difference between both traces was calculated (thin line).
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Overall, under the conditions of razor-blade isolated retina it was impossible to record a full ERG with a “healthy” b-wave component, as it was routinely observed for the isolated bovine retina in the same setup system. Therefore, the isolation protocol was changed completely.
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2.1.2. Retina isolation under more gentle conditions followed by a preincubation period
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The isolation of the murine retina was changed in a way that mechanical stress was reduced. In a well documented approach, the murine retina was isolated by opening up the eye bulb from the anterior side by dissecting the cornea, and by explanting the eye lens first [14]. We assume that the rotating razor blade in the former procedure may have introduced too much mechanical tension on the retina leading to a trauma and a loss of full transretinal signalling capacity. The new isolation procedure can be followed up in a detailed animation, which is available in the internet as a supplement [14]. In short, enucleated murine eyes (Fig. 2)\n\t\t\t\t\t
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Figure 2.
Isolation of murine retina segments for ERG-recordings by opening up the eye bulb from the front side of the eye. The pictures are taken from a detailed animation (generated by Nadeen Albanna), which can be watched in the supplement of the related publication [14].A. The extirpated eye cup was initially treated with a 27 gauge needle from the front side to relief the tension. The cornea is used to hold the eye cup by fixing it via a lancette. The cornea will be partially separated. B. A triangled cut is incised into the sclera, reaching down to the ora serrata region. A forceps is moved through the triangle cut to remove the iris (for details of the used tools refer to [14]). C. After removing the iris, the lens will be taken off, and the opened eye is gently moved within the nutrient solution to tear off gently the retina from the underlying pigment epithelium. D. Next, two forceps are used to open up the sclera layers by tearing it apart at the site of initial incision. The retina usually stays intact, and can be cut into up to 4 - 6 pieces. E. The white supporting lever arm is connected with a 3 mm in diameter facing ring, to which the retina can be attached. It is held by surface tension to the ring and covers the central hole of 1 mm diameter. F. The retina-loaded support system is moved to the recording chamber, and docked into the central hole of the gasket. The recording chamber is closed by rubber rings, glas plates and interconnecting metal rings.
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were placed into nutrient solution, fixed by a lancette and opened from the front side first by punching a tiny hole through the cornea to relieve the aqueous humour from the anterior and posterior chamber of the eye, and thus, to reduce the tension (Fig. 2A). Thereafter, the cornea was removed, and the iris disconnected, and a tiny triangle shaped incision was made into the sclera (Fig. 2B) for an easier separation later of the proximal eye cup, and for the immediate introduction of a small forceps. Finally, the lens was carefully removed (Fig. 2C). Consecutively, the opened eye-cup was held and separated apart by a forceps in order to detach the retina from the pigment epithelium by repetitive moving in the nutrient solution (Fig. 2D). The successive separation of the retina from the pigment epithelium has to be performed gently, and is supported by the cutting of the sclera layers from the outside. Finally, the isolated retina may be divided into 4 - 6 segments.
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One of the posterior retina segments was finally mounted on a plastic mesh occupying the centre of the perfusing chamber by using a supporting tool (Fig. 2E). The ring, fixed by the submerged lever tool, is loaded with a retina segment, which was stored floating in the oxygenized nutrient solution. It is touched with the forceps at the region where formally the fibres of the N. opticus had left the eye cup. The retina segment adheres by itself and the supporting lever is turned upside down to move the retina loaded ring into the holder of the recording chamber (Fig. 2F). The view from the underlying nylon mesh further visualizes one of the two silver/silver-chloride electrodes, which are on both sides of the recording chamber. After closing the chamber by two gaskets and two glasses, the nutrient solution is perfused over the front and the rear side (Fig. 2F) of the recording chamber.
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Based on the more gentle isolation procedure, full ERG recordings could be achieved, and optimal conditions for the recordings for mice were summarized and published [14]. For example, light intensity for scotopic ERG recordings was as low as 6.3 mlx for the bovine retina but 10-fold higher for the murine retina.
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ERG recordings even in the presence of low NiCl2 concentrations (up to 50 µM) could be easily followed up for several hours without loosing a full b-wave response (Fig. 3B).
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Figure 3.
Murine ERGs, which were recorded after gentle retina isolation and a 4 hour preincubation period. Light flashes were given at 63 mlx for 0.5 sec (see bar under the ERGs). Temperature was 27.5 °C. Flow rate for nutrient solution (Sickel solution) was 2 ml/min. A. Early registration of ERG in the absence of NiCl2. Recording was started 30 min after loading the recording chamber. B. Full ERGs after NiCl2 superfusion. Superposition of ERG traces after 60 min (red line, 10 µM NiCl2), 86 min (black line, 15 µM NiCl2), 150 min (blue line, 50 µM NiCl2), and 215 min (green line, 50 µM NiCl2).
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Usually, the murine retina needed a while before a full ERG was seen. Early ERGs (Fig. 3A) were characterized a dominant a-wave, and the b-wave developed during the next 30 min [14]. The superimposed traces in Fig. 3B reveal that over time (60 – 215 min) the amplitude did not decrease much, but the implicit time got shorter and the shape of the b-wave changed indicating that the transretinal signalling varied (compare to later results with the different mouse mutants, especially the ERGs from Cav2.3-deficient mice, which are lacking the later fraction of the b-wave [9]).
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The major goal for murine ERG-recording was the demonstration of an increase of the b-wave amplitude after the superfusion of low NiCl2 (10 – 30 µM). Under these conditions (15 µM NiCl2) the ERG b-wave amplitude of the isolated bovine retina was increased up to 1.5-fold [3]. For the bovine retina it was concluded that the pharmacoresistant Ca2+ channel Cav2.3 may trigger the GABA release necessary for reciprocal signalling backwards to the bipolar neurons [10]. This conclusion should be validated or disproven in mouse models with selective Ca2+ channel inactivation, either lacking Cav2.3 or Cav3.2 or even both subunits of voltage-gated Ca2+ channels. Therefore, the murine retina had to be isolated in a way that not only the basal signal transduction but also the reciprocal signalling would be conserved over time. Under these conditions, retinas from Cav2.3-competent and Cav2.3-deficient mice were isolated and their sensitivity towards NiCl2 (15 and 30 µM) was analysed and compared between different genotypes [14]. For the ERGs from Cav2.3-competent mice, the data for 30 µM NiCl2 are summarized (Tab. 1).
\n\t\t\t\t\t
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\n\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\t
Exp. #
\n\t\t\t\t\t\t\t\t
Before NiCl2: Amplitude, µV
\n\t\t\t\t\t\t\t\t
After NiCl2, 30 µM: Amplitude, µV
\n\t\t\t\t\t\t\t\t
Washout: Amplitude, µV
\n\t\t\t\t\t\t\t\t
Ratio 1: under NiCl2 before NiCl2\n\t\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\t
Ratio 2: under NiCl2 after Washout
\n\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\t
1
\n\t\t\t\t\t\t\t\t
6,15
\n\t\t\t\t\t\t\t\t
11,18
\n\t\t\t\t\t\t\t\t
6,87
\n\t\t\t\t\t\t\t\t
1,82
\n\t\t\t\t\t\t\t\t
1,63
\n\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\t
2
\n\t\t\t\t\t\t\t\t
14,88
\n\t\t\t\t\t\t\t\t
16,63
\n\t\t\t\t\t\t\t\t
11,58
\n\t\t\t\t\t\t\t\t
1,12
\n\t\t\t\t\t\t\t\t
1,44
\n\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\t
3
\n\t\t\t\t\t\t\t\t
4,97
\n\t\t\t\t\t\t\t\t
7,63
\n\t\t\t\t\t\t\t\t
4,65
\n\t\t\t\t\t\t\t\t
1,54
\n\t\t\t\t\t\t\t\t
1,64
\n\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\t
4
\n\t\t\t\t\t\t\t\t
9,70
\n\t\t\t\t\t\t\t\t
16,2
\n\t\t\t\t\t\t\t\t
9,28
\n\t\t\t\t\t\t\t\t
1,67
\n\t\t\t\t\t\t\t\t
1,75
\n\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\t
5
\n\t\t\t\t\t\t\t\t
5,90
\n\t\t\t\t\t\t\t\t
9,0
\n\t\t\t\t\t\t\t\t
6,23
\n\t\t\t\t\t\t\t\t
1,53
\n\t\t\t\t\t\t\t\t
1,44
\n\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\t
6
\n\t\t\t\t\t\t\t\t
9,82
\n\t\t\t\t\t\t\t\t
13,91
\n\t\t\t\t\t\t\t\t
10,85
\n\t\t\t\t\t\t\t\t
1,42
\n\t\t\t\t\t\t\t\t
1,28
\n\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\t
7
\n\t\t\t\t\t\t\t\t
6,55
\n\t\t\t\t\t\t\t\t
8,39
\n\t\t\t\t\t\t\t\t
7,44
\n\t\t\t\t\t\t\t\t
1,28
\n\t\t\t\t\t\t\t\t
1,13
\n\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\t
8
\n\t\t\t\t\t\t\t\t
24,98
\n\t\t\t\t\t\t\t\t
20,27
\n\t\t\t\t\t\t\t\t
22,72
\n\t\t\t\t\t\t\t\t
0,81
\n\t\t\t\t\t\t\t\t
0,89
\n\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\t
9
\n\t\t\t\t\t\t\t\t
98,30
\n\t\t\t\t\t\t\t\t
142,8
\n\t\t\t\t\t\t\t\t
111,2
\n\t\t\t\t\t\t\t\t
1,45
\n\t\t\t\t\t\t\t\t
1,23
\n\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\t\tMean:\n\t\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\t
1,40
\n\t\t\t\t\t\t\t\t
1,38
\n\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\t
Stdev
\n\t\t\t\t\t\t\t\t
0,3
\n\t\t\t\t\t\t\t\t
0,28
\n\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\t
SEM
\n\t\t\t\t\t\t\t\t
0,1
\n\t\t\t\t\t\t\t\t
0,09
\n\t\t\t\t\t\t\t
\n\t\t\t\t\t\t
Table 1.
Development of b-wave amplitude after a 4 hour preincubation period for Cav2.3-competent mice by superfusing nutrient solution (= before NiCl2), 30 µM NiCl2 for 30 min (= after NiCl2), and by washing out the NiCl2 (= washout). Note, such a reversible increase of the b-wave amplitude, as shown for 9 experiments, was not always observed. In nearly the same number of experiments, no significant increase was detected, which may be attributed to the 4 hour preincubation period, during which reciprocal signalling was partially reduced or completely lost for unknown reasons.
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As the full ERG-response with “healthy” b-waves was only achieved after a prolonged incubation period of 4 hours, we were afraid and realized that the capacity for maximal reciprocal signalling was partially or fully lost during such a preincubation. The consecutive large scatter for Ni2+-mediated stimulation of the b-wave amplitude led us to conclusion to modify the recording procedure for a more stable transretinal signalling.
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2.1.3. Retina isolation under gentle conditions without a preincubation period
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To overcome any variable loss of reciprocal signalling, the murine retina was isolated again by the more gentle procedure as outlined before [14]. The adaptation period however was skipped to avoid any loss of reciprocal signalling. Early ERG recordings, which were still dominated by the photoreceptor response, were digitalized and stored, and mean values were calculated for the response before adding any NiCl2. Thereafter, NiCl2 superfusion (15 µM) was initiated within the first 15 – 20 min after introducing the retina segments into the recording chamber. The NiCl2 application routinely lasts for 30 min, a time, after which a new equilibrium was reached and stable full ERG responses were recorded. From those ERG traces a mean trace curve was calculated and the mean ERG trace without NiCl2 superfusion was subtracted from the mean trace under NiCl2. Such difference-ERG traces were normalized and compared between different genotypes [9].
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To our surprise, even the photoreceptor response differed between the two mouse lines either lacking Cav3.2 (including the double knockout) and the Cav2.3-competent or -deficient mouse line. The larger hyperpolarization at the beginning of each experiment for Cav3.2-deficient mice or double knockout mice was the reason that the amplitude of the difference–ERG was much larger than in retinas from Cav2.3-competent or –deficient mice. Most interesting, however, was the result deduced from implicit times of the normalized difference-ERGs. Obviously, Cav2.3 / R-type and Cav3.2 / T-type Ca2+ channels may contribute to different fractions of the signal transduction in the retinal network. In Cav2.3-deficient mice, the implicit time for the apparent b-wave is significantly shorter (346 ± 12 ms; n = 8 retinas) than in Cav2.3-competent mice (474 ± 27 ms; n = 5 retinas; p < 0.001), which implies that the later b-wave fraction, which is missing in the Cav2.3-deficient mice, would be carried in Cav2.3-compentent mice by the pharmacoresistant R-type channel triggering synaptic neurotransmitter release. This interpretation is in line with the assumption [10] that Cav2.3 may act in the synapse of a third order neuron, e.g. after the bipolar – amacrine synapse, while Cav3.2 may rather be responsible for a T-type triggered neurotransmitter release in the bipolar – amacrine synapse. T-type Ca2+ currents were routinely identified in these bipolar neurons [15-17].
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The inactivation of Ca2+ channel genes could also disturb the overall retinal organisation. However, at least the inactivation of Cav2.3 does not disturb macroscopic structures in the retina as evaluated by histochemical staining (Fig. 4). Visual inspection and quantification of the thickness for retinal layers confirmed that no massive loss of neurons has occurred, which may also be true for the other knockout models.
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2.2. Tricine-containing nutrient solution to chelate traces of divalent heavy metals
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The use of Ni2+ as Ca2+ channel antagonist for R- and T-type Ca2+-channels has a long tradition [18;19]. Only recently zinc and copper ions have been recognized as important endogenous modulators of neuronal excitability [20], and the most Ni2+-sensitive Ca2+ channels were also characterized for its capability to be blocked by these native heavy metal cations [21-24]. The disturbance of their homoeostasis may be responsible for several neurological diseases as for example Morbus Alzheimer [25;26]. Much more is known for the physiological role of Zn2+ than for Cu2+, which proves to be effective (submicromolar) even in lower concentrations than Zn2+.
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Figure 4.
Comparison of thicknesses in retinal cross sections obtained from control and Cav2.3-deficient mice. Light micrographs were taken from thicker (more central) regions and from thinner (more peripheral) regions away from the optical nerve head. Each layer is identified by its abbreviations (Rec = photoreceptors; ONL = outer nuclear layer; OPL = outer plexiform layer; INL = inner nuclear layer; IPL + GCL: inner plexiform layer and granular cell layer were summarized for quantification; data were produced by Mehran Maghsoodian and Petra Müller). A. Retinal sections from control female mice at the age of 34 month. B. Retinal sections from Cav2.3-deficient female mice at the same age of 34 month. C & D.: Quantification of thicknesses for individual retinal layers for controls and KO’s.
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The effect of ZnCl2 (10 – 15 µM) on transretinal signalling resembles the effect of NiCl2, which was investigated in detail for the isolated bovine retina [11].
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The second most abundant trace element in the human body is represented by Zn2+. In total it reaches up to two grams in adult humans. Most Zn2+ in the body is located intracellularily. But as only a small labile portion in the liver may be available during Zn2+ deficiency, a regular dietary supply of Zn2+ during growth and aging is needed [27].
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After Zn2+ deficiency, the multitude of physiological roles for Zn2+ are best seen, which include anorexia, retarded growth, weight loss, impaired immune function, delayed sexual maturation, testicular atrophy, epidermal hyperkeratinization, alopecia, hypogeuisa, and night blindness [27;28]. In ocular tissues, the concentration of Zn2+ is unusually high when compared to other tissues. Zn2+ was localized in retina, chorioid, ciliary body, iris, optic nerve, sclera, cornea, and lens [27;29].
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As soon as the function of Cu2+ would also be investigated, contaminations of submicromolar heavy metal cations may count for the validity of experiments in the future. To test a well known buffer system, which can be used to calibrate the desired cation concentration, tricine was added in various amounts (15 mM, 10 mM, and 5 mM) to the normally used nutrient solution. The bovine retina was used in these experiments. While 15 and 10 mM inhibited the b-wave response, no substantial change was observed at 5 mM tricine. Sometimes we observed a slight decrease of the b-wave amplitude, which may be attributed to heavy metal contaminations in the nutrient solution. After a chelation of traces by tricine, the effect of NiCl2 (15 µM) was analysed leading to a similar and transient increase of the b-wave response (Fig. 5).
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Figure 5.
ERG recordings from the isolated bovine retina. After isolation of a standard retina segment, the retina was equilibrated for at least 30 min. A. During the superfusion of 5 mM tricine buffer added to the normal nutrient solution, no lasting change of b-wave response was observed. Tricine was washed and exchanged to normal nutrient solution including NiCl2 (15 µM), leading to a transient increase of the b-wave response. B. Implicit times increase mostly after superfusion with NiCl2.
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\n\t\t\t
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2.3. Stability testing for murine ERG responses under high intensity light conditions
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So far, murine ERGs were recorded under low light intensity (63 mlx for 0.5 sec). But the testing of higher light intensities may be needed, because reciprocal signalling should be more pronounced at elevated light intensities, if the reciprocal signalling participates in light/dark adaptation. Therefore, we analysed the effect of increasing light intensities on the photoreceptor response of the isolated murine retina (Fig. 6).
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Figure 6.
Murine ERGs were recorded after gentle retina isolation without a preincubation period. Light flashes were given in 3 min intervals interrupted by darkness. Light stimuli were at various light intensities for 0.5 sec (light bar at the bottom of each figure). Temperature was 27.5 °C. In some panels the background light intensity (= H), and the stimulus intensity (= R) is given. A. Early registration of ERGs in the absence of NiCl2. Recording was started within 30 min after loading the recording chamber. B. Light intensity – response curve for the apparent a-wave amplitude (data taken from the ERG records in panel A). The semi-logarithmic plot shows a linear increase up to the highest light intensity tested (2 mlx – 20 lx). C. Superposition of ERG traces before (solid black line) and 15 min after light adaptation (fine dashed red line) under continuous light (200 mlx). Stimulus light intensity was 630 mlx. Note the minor reduction of the apparent a-wave may be attributed to a slowly increasing b-wave, which gets more pronounced after NiCl2 application (see Fig. 7). D. Time course of light adaptation under the conditions as described in panel C.
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Figure 7.
continued). E. After the light adaptation for 15 min (see panel D), dark adaption was tested for the stability of the photoreceptor response. Superposition of ERG traces 6 min (solid black line) and 15 min after dark adaptation (fine dashed red line). Stimulus light intensity was 63 mlx. Again, a minor reduction of the apparent a-wave may be attributed to a slowly increasing b-wave, which gets more pronounced after NiCl2 application (see Fig. 7). Note the stimulus light intensity under scotopic conditions was 1/10th of that during light adaptation in panel D. F. Time course of the photoreceptor response during 15 min dark adaptation using a stimulus light intensity of 6.3 mlx (at 0 and 3 min) and of 63 mlx for the remaining light flashes. Note the flash light intensity during the first 6 min was reduced to ensure dark adaptation to start fast. G. Superposition of ERG responses (dominated by a-wave) from different light intensities (2 mlx – 20 lx). Especially during higher light intensities (200 mlx – 20 lx) a small b-wave gets visible. H. Light intensity – response curve for the apparent a-wave amplitude (filled circles; data taken from the ERG records in panel G). The semi-logarithmic plot shows a near linear increase up to the highest light intensity tested (2 mlx – 20 lx), which reveals lower apparent a-wave amplitudes as during the first regime (open circles; data are identical to panel B). Threshold values for light intensities are similar in both regimes.
\n\t\t\t\t
During an experimental regime of early dose-response (Fig. 6A, 6B), light (Fig. 6C, 6D) and dark adaptation (Fig. 6E, 6F), and late dose-response (Fig. 6G, 6H), it gets obvious that the isolated murine retina yields rather stable photoreceptor responses, which are only slightly reduced by the slowly growing b-wave. A faster development of the b-wave response can be achieved by adding NiCl2. The superfusion of 15 µM NiCl2 leads within 30 min to a fast increase of the developing b-wave. The ERG traces before and after NiCl2 superfusion indicate that during this period b-wave gets maximally increased (Fig. 7), as reported recently [9].
\n\t\t\t\t
Figure 8.
Development of b-wave by NiCl2 application. Superposition of ERG traces before (black solid line) and after NiCl2 superfusion (15 µM; red dashed line). The increase is still half-maximal within 6 min of NiCl2 superfusion. Note, after full development of b-wave, it superimposes nearly completely the a-wave response, as it is expected for a light intensity of 63 mlx (compare [14]). H = background in darkness in between each light flash. R = stimulus intensity.
\n\t\t\t\t
To test the stability of the isolated murine retina for its transretinal signalling capability (Fig. 8), the b-wave amplitude was recorded and used as the readout during similar experiments as it was performed for photoreceptor responses. The light induced stress was even increased by recording the light intensity – response curve under continuous background light first at 630 mlx (not shown) and thereafter at 2000 mlx (Fig. 8E, 8F).
\n\t\t\t\t
Figure 9.
Murine ERGs were recorded after gentle retina isolation without a preincubation period in the presence of 15 µM NiCl2. Light flashes were given after 3 min at various light intensities for 0.5 sec. Background illumination as indicated in each panel. Temperature was 27.5 °C. A. Recording was continued without delay after the b-wave was reached (Fig. 7). Superposition of individual ERG traces at the indicated light intensities. Background was in darkness. B. Light intensity – response curve for the b-wave amplitude (data taken from the ERG records in panel A). The semi-logarithmic plot shows an optimum of the b-wave response between 63 and 630 mlx. C. Superposition of ERG traces recorded at 63 mlx stimulus light before (solid black line) and 15 min of light adaptation (fine dashed red line) under continuous light (200 mlx). Stimulus light intensity was 63 mlx. Note the ERG traces are nearly identical at both time points. D. Time course of light adaptation for apparent a- and b-wave under the conditions as described in panel C.
\n\t\t\t\t
Figure 10.
continued). E. After the light adaptation for 15 min, the light intensity-response was recorded first with 630 mlx background light (not shown) and next with 2000 mlx background light. Superposition of ERG traces for the stimulus light intensities as indicated. F. Light intensity – response curve for the b-wave amplitude (data taken from the ERG records in panel E). The semi-logarithmic plot shows an optimum of the b-wave response at 200 mlx.
\n\t\t\t\t
Increasing the light intensity beyond 63 to 630 mlx caused a reduction of the b-wave amplitude as reported in the literature, and reflecting the process of light adaptation. Consecutively, the apparent a-wave amplitude gets increased (Fig. 8B). For the b-wave, the implicit time gets shorter during increased light intensities. Interestingly, under these conditions of 15 min continuous background light (200 mlx), the stability of the b-wave response is remarkable. Even more astonishing is the observation that under 630 and 2000 mlx background light, the b-wave responses continue to be very pronounced tolerating the increased light intensity at the recording chamber.
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\n\t\t\t
3. Conclusion
\n\t\t\t
The transfer of the ERG recording technique from the bovine retina model to the various murine knockout models is possible, and the higher sensitivity of the murine retina towards ischemia maybe overcome by a more gentle preparation technique as outlined in detail [14]. Future investigations of the murine retina from different mouse models may benefit from such an isolation procedure.
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Besides ERG recordings additional electrophysiological recording techniques (e.g. patch clamp registration) will be needed to characterize signalling through retinal circuits.
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\n\t
Acknowledgments
\n\t\t\t
We thank Priv.-Doz. Dr. Matthias Lüke, Dr. Siarhei A. Siapich for their excellent and permanent assistance during the work with the bovine retina, which is an important prerequisite for the transfer to the murine retina. The authors would also like to thank Nadeen Albanna (animation), Renate Clemens (genotyping and breeding of mice), Mehran Maghsoodian and Petra Müller (retinal IHC) for their support, as well as the animal keepers of the central facility for their excellent and permanent assistance. This work was financially supported by the Köln Fortune Programme of the Faculty of Medicine, University of Cologne (to MA, WA and MB) and by the Center for Molecular Medicine Cologne (CMMC, to TS and JH, Faculty of Medicine, University of Cologne).
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\n',keywords:null,chapterPDFUrl:"https://cdn.intechopen.com/pdfs/17270.pdf",chapterXML:"https://mts.intechopen.com/source/xml/17270.xml",downloadPdfUrl:"/chapter/pdf-download/17270",previewPdfUrl:"/chapter/pdf-preview/17270",totalDownloads:2184,totalViews:153,totalCrossrefCites:0,totalDimensionsCites:0,totalAltmetricsMentions:0,introChapter:null,impactScore:0,impactScorePercentile:34,impactScoreQuartile:2,hasAltmetrics:0,dateSubmitted:"November 15th 2010",dateReviewed:"June 10th 2011",datePrePublished:null,datePublished:"August 9th 2011",dateFinished:null,readingETA:"0",abstract:null,reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/17270",risUrl:"/chapter/ris/17270",book:{id:"360",slug:"electroretinograms"},signatures:"Alnawaiseh Maged, Albanna Walid, Banat Mohammed, Abumuaileq Ramzi, Hescheler Jürgen and Schneider Toni",authors:[{id:"44215",title:"Prof.",name:"Toni",middleName:null,surname:"Schneider",fullName:"Toni Schneider",slug:"toni-schneider",email:"toni.schneider@uni-koeln.de",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"44248",title:"Dr.",name:"Walid",middleName:null,surname:"Albanna",fullName:"Walid Albanna",slug:"walid-albanna",email:"walidalbanna@yahoo.de",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"44250",title:"Dr.",name:"Mohammed",middleName:null,surname:"Banat",fullName:"Mohammed Banat",slug:"mohammed-banat",email:"aboalhassan83@hotmail.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"44252",title:"Mr",name:"Maged",middleName:null,surname:"Alnawaiseh",fullName:"Maged Alnawaiseh",slug:"maged-alnawaiseh",email:"magedbonn@yahoo.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"44254",title:"Prof.",name:"Jürgen",middleName:null,surname:"Hescheler",fullName:"Jürgen Hescheler",slug:"jurgen-hescheler",email:"j.hescheler@uni-koeln.de",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null}],sections:[{id:"sec_1",title:"1. Introduction ",level:"1"},{id:"sec_2",title:"2. Optimization of murine ERG recordings and applications ",level:"1"},{id:"sec_2_2",title:"2.1. Development of methods to record full murine ERGs for basal and reciprocal signalling ",level:"2"},{id:"sec_2_3",title:"2.1.1. Retina isolation by a rotating razor blade ",level:"3"},{id:"sec_3_3",title:"Table 1.",level:"3"},{id:"sec_4_3",title:"2.1.3. Retina isolation under gentle conditions without a preincubation period",level:"3"},{id:"sec_6_2",title:"2.2. Tricine-containing nutrient solution to chelate traces of divalent heavy metals ",level:"2"},{id:"sec_7_2",title:"2.3. Stability testing for murine ERG responses under high intensity light conditions",level:"2"},{id:"sec_9",title:"3. 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A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHescheler\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWeiergräber\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSchneider\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2008 The dihydropyridine isradipine inhibits the murine but not the bovine A-wave response of the electroretinogram. Acta Ophthalmol.; 86\n\t\t\t\t\t676\n\t\t\t\t\t682 .\n\t\t\t'},{id:"B13",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHanawa\n\t\t\t\t\t\t\tI.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTateishi\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1970 The effect of aspartate on the electroretinogram of the vertebrate retina. 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University of CologneInstitute of Neurophysiology & Center for Molecular Medicine Cologne (CMMC), Germany
'}],corrections:null},book:{id:"360",type:"book",title:"Electroretinograms",subtitle:null,fullTitle:"Electroretinograms",slug:"electroretinograms",publishedDate:"August 9th 2011",bookSignature:"Gregor Belusic",coverURL:"https://cdn.intechopen.com/books/images_new/360.jpg",licenceType:"CC BY-NC-SA 3.0",editedByType:"Edited by",isbn:null,printIsbn:"978-953-307-383-5",pdfIsbn:"978-953-51-6445-6",reviewType:"peer-reviewed",numberOfWosCitations:35,isAvailableForWebshopOrdering:!0,editors:[{id:"44595",title:"Dr.",name:"Gregor",middleName:null,surname:"Belusic",slug:"gregor-belusic",fullName:"Gregor Belusic"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"1094"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},chapters:[{id:"17262",type:"chapter",title:"Electroretinography",slug:"electroretinography",totalDownloads:6284,totalCrossrefCites:1,signatures:"Kyle Wolpert and Stephen Tsang",reviewType:"peer-reviewed",authors:[{id:"44240",title:"Dr.",name:"Stephen",middleName:null,surname:"Tsang",fullName:"Stephen Tsang",slug:"stephen-tsang"},{id:"60890",title:"Mr.",name:"Kyle",middleName:null,surname:"Wolpert",fullName:"Kyle Wolpert",slug:"kyle-wolpert"}]},{id:"17263",type:"chapter",title:"Electroretinograms and Normative Data",slug:"electroretinograms-and-normative-data",totalDownloads:3948,totalCrossrefCites:4,signatures:"Rustum Karanjia, Martin W. ten Hove and Stuart G. 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1. Introduction
Henri Roger first gave us the term “parasomnia” in 1932 [1]. Subsequently, parasomnias have been extensively described and classified into non-REM-related parasomnias and REM-related parasomnias, so designated for the sleep stage from which the parasomnia emerges [2]. Though there is overlap in treatment options for the parasomnias, treatment most often follows semiology and pathophysiology. Sleep-related movement disorders are likewise varied in their presentations [3]. The treatment of parasomnias and sleep-related movement disorders relies on removal or avoidance of precipitants, behavioral techniques, prosthetic or dental devices, as well as, medications. Multi-pronged approaches including behavioral techniques in addition to medications may be most effective. The use of medication is still a necessary component of care in illnesses with significant immediate and long-term complications. This includes serious complications to the individual suffering from these sleep disorders, as well as, their bed partners and others within their circle of family and friends. In the body of this chapter, I will review the parasomnias and sleep-related movement disorders with behavioral and pharmaceutical approaches to treatment. Where behavioral approaches alone are much preferred, this chapter will not delve into the physiology, psychology or known pathology of the disorder. Where pharmaceutical approaches are common, the chapter will briefly discuss the pathophysiology of the disorder and the desirable treatment strategies from clinical studies and expert opinion. Drug classes will be fully addressed in individual sections. These sections will discuss the pharmacokinetics, pharmacodynamics, and adverse effect profiles of the more commonly prescribed drugs within these classes, comparing them by popularity, desirable properties, and risks of adverse events. Lastly, in the conclusion this chapter will briefly review the current controversies of pharmacologic treatment.
2. The parasomnias
The parasomnias can be divided into the non-REM parasomnias, the REM parasomnias, the overlap parasomnias, and others which defy definition by sleep stage [4]. To best understand these differences, it is necessary to have some knowledge of role sleep plays in normal physiology. The sleep stages show a cyclic pattern of light sleep (N1) proceeding to common sleep (N2), then to slow wave or deep sleep (N3) and finally rapid eye movement (REM) sleep. The cycles gradually change with more N3 sleep in the first half of the night and more REM sleep in the second half of the night. These sleep cycles have been shown to serve multiple physiologic and homeostatic functions, but for the purposes of this chapter, deep sleep (N3) has been associated with the arousal disorders (confusional arousals, sleep walking, and sleep terrors) and REM sleep has been associated with dream enactment or REM sleep behavior disorders and nightmares. Each of these disorders demand therapeutic approaches that may not work for the others, i.e., sedation may be helpful (at least temporarily) for REM sleep parasomnias, but be counter-productive in the arousal disorders.
2.1 Clinical evaluation
The clinical differentiation of the parasomnias demands a careful and complete history and physical exam. Witnesses to and video recordings of the parasomnia are invaluable. Precipitants for parasomnias include sleep-related breathing disorders, sleep deprivation and insufficient sleep for age, emotional trauma and chronic mental illness, narcolepsy, endocrine disorders including hypothyroidism, diabetes, and perimenstrual distress, degenerative brain disorders, such as Parkinsonism and dementia with Lewy bodies, head injury and stroke, epileptic and non-epileptic seizures, and medications including lithium, neuroleptics, anticholinergics, antidepressants, sedative-hypnotics, opioids, and various recreational drugs including alcohol. Very high dose caffeine consumption is another concern as is current marijuana use and the use of illegal drugs such as fentanyl and cocaine. A family history of parasomnia may or may not be present on initial evaluation. A thorough physical examination may reveal findings consistent with sleep apnea or respiratory compromise, thyroid enlargement or tenderness, neurologic deficits or psychiatric abnormalities. Given the spectrum of parasomnias and varying etiologies underlying them, if the clinician’s assessment misses an important precipitant or co-morbidity, pharmacologic management will likely fail or cause adverse effects.
2.2 Arousal disorders
The arousal disorders arise out of deep sleep (N3) and are felt to represent parasomnias emerging from difficulty completely awaking from sleep. These disorders consist predominantly of confusional arousals, sleep walking and sleep terrors and effect children under 11 years of age more than adults. There is a wide variance in reports of prevalence of arousal disorders from 9–45% of children [2, 4, 5, 6, 7]. The lifetime prevalence in individuals over 15 years of age falls to 2.9% to 4.2%. The diagnostic criteria are presented in Table 1. Genetic factors [8], infections, sleep deprivation, and obstructive sleep apnea [9] can all be predisposing factors, whose elimination may prevent recurrent events. With the exception of epilepsy, pharmacotherapy may not be effective and may actually worsen symptoms [10]. Reassurance and behavioral approaches such as creating a safe sleeping environment, anticipatory or scheduled awakenings, cognitive behavioral therapy [10, 11], and hypnosis [12] are among the non-pharmacologic options.
A.
Recurrent episodes of incomplete awakening from sleep
B.
Inappropriate or absent responsiveness to efforts of others to intervene or redirect the person during the episode
C.
Limited (e.g., a single visual scene) or no associated cognition or dream imagery
D.
Partial or complete amnesia for the episode
E.
The disturbance is not better explained by another sleep disorder, mental disorder, medical condition, medication or substance use
Table 1.
General diagnostic criteria for disorders of arousal (criteria A-E must be met) [2].
Notes
The events usually occur during the first third of the major sleep episode
The individual may continue to appear confused and disoriented for several minutes or longer following the episode.
Use of drugs in the developing brain is a concern for pharmacologists due to the extreme plasticity of immature neuronal networks. Another concern for the use of pharmaceutical agents in children is the tendency of the disorders to resolve spontaneously as a child matures. Proserpio et al. [13] laid out four indications for initiation of pharmacotherapy. The first is persistence of frequent episodes despite elimination of predisposing factors. The second is high risk of injury. The third is significant functional impairment, and the fourth is potential legal consequences. In the presence of 2–4, there may not be time to pursue behavioral approaches to management.
The most frequently used drugs for arousal disorders are the benzodiazepines. Antidepressant drugs have been used less frequently. Of note, none of these drugs has an FDA indication for their use in arousal disorders or have any large-scale controlled studies of their efficacy. The very long-acting benzodiazepine, clonazepam, has been the most frequently used agent [14, 15, 16] though other benzodiazepines including alprazolam and diazepam have been used in adult sleep terrors and sleepwalking. Antidepressant drugs including sertraline, paroxetine [17], clomipramine, imipramine [18], and trazodone [19] have been used in small case series. Case reports have also shown efficacy in the treatment of arousal disorders for melatonin [20, 21], hydroxytryptophan [22, 23], and ramelteon [24].
2.2.1 Sleep-related Hypermotor epilepsy
Nocturnal frontal lobe epilepsy, otherwise known as sleep-related hypermotor epilepsy, can present as recurrent, intractable confusional arousals [25, 26]. Routine polysomnography is not as helpful in differentiating an arousal disorder from sleep-related hypermotor epilepsy as is video-electroencephalographic recording in an inpatient epilepsy monitoring center. While this is an expensive evaluation option, home video recording via cell phone camera, stereotypical behavior of the events, frequency up to nightly, persistence into adulthood, and the presence of a brain disorder can guide a clinician’s decision to proceed [27]. In the author’s experience in a busy university sleep clinic, less than 5% of adult patients presenting with arousal disorders are referred for epilepsy monitoring, however, 30% of the patients who were referred for epilepsy monitoring were diagnosed with likely or definite sleep-related hypermotor epilepsy. As a side note, treatment trials with anti-seizure drugs in these patients are not helpful for differentiation, as the pharmacologic control of sleep-related hypermotor epilepsy is often challenging.
2.3 REM parasomnias
The REM sleep related parasomnias most prominently include REM sleep behavior disorder and nightmare disorder [2]. REM sleep behavior disorder is often managed with medications, but nightmare disorder is more often treated with behavioral interventions. The prevalence of REM sleep behavioral disorder (REMSBD) is unknown but has been estimated to be 0.38% of the general population, increasing in frequency with age [28, 29]. It is more prevalent in men and usually emerges after age 50 [2]. There is a prominent association in older patients with the synucleinopathies [30]. The differential in younger patients can be quite wide. This parasomnia can be co-morbid with narcolepsy, brain tumors, antidepressant medications, and neurodevelopmental disorders [2]. Severe obstructive sleep apnea can cause dream enactment that mirrors REM sleep behavior disorder [31]. A variety of medications have been implicated in the precipitation of REM sleep behavior disorder. Antidepressants including venlafaxine, mirtazapine, and selective serotonin reuptake inhibitors, but not the dopamine reuptake inhibitor bupropion [32], can precipitate REMSBD. Medications including beta-blockers, anticholinesterase inhibitors, and selegiline have been reported to precipitate REMSBD [2]. Nightmares may occur in 60–75% of children; however, frequent nightmares are far less common occurring in only 1–5% of children [33]. Post-traumatic stress disorder is a common cause of nightmares in adults [34], but 2–8% of the general population may have troublesome nightmares. Various pharmaceuticals can precipitate nightmares. These include drugs affecting the neurotransmission of norepinephrine, serotonin, and dopamine such as antidepressants, antihypertensives, and dopamine receptor agonists. In addition, the withdrawal of a REM sleep suppressant can precipitate the complaint of nightmares. Varenicline, a nicotinic antagonist, may commonly induce nightmares [35]. The clinical management of nightmares includes removing as many predisposing factors as possible.
The chapter will not discuss parasomnias, such as exploding head syndrome and sleep related hallucinations, that are treated with reassurance and very rarely with drugs. Sleep enuresis may occur in 15–20% of five-year-old’s [2]. It is more common in boys. Non-pharmacologic treatments are superior when the etiology is obstructive sleep apnea [36], ingestion of high doses of caffeine or psychosocial stressors. Nightly desmopressin is used when indicated for frequent intractable sleep enuresis. Pharmacologic management is necessary for urinary tract infections, diabetes insipidus, diabetes mellitus, or nocturnal epilepsy [2]. Fortunately, improvement occurs with age in these children.
3. Sleep related movement disorders
The sleep related movement disorders consist of restless leg syndrome, periodic limb movement disorder, sleep related leg cramps, sleep related bruxism, the sleep related rhythmic movement disorders, sleep related myoclonus at sleep onset, propriospinal myoclonus at sleep onset [2]. Benign sleep myoclonus of infancy is different in that more than half of these infants have neonatal opioid withdrawal syndrome [37]. Sleep related rhythmic movement disorders, sleep related myoclonus at sleep onset, and propriospinal myoclonus at sleep onset, and benign sleep myoclonus of infancy are very rarely treated with pharmaceuticals once the diagnosis is made. Reassurance and building a safe bedroom environment are the treatments of choice. Likewise, sleep related bruxism (SRB) is best treated with oral devices that protect the teeth. Sleep related bruxism has its highest incidence in childhood, occurring in 14–17% of children before decreasing over the life span to 3% of older persons [38]. Sleep related breathing disorders are often co-morbid with sleep bruxism [39] though the relationship is unclear. More recently, botulinum toxin has been used for intractable sleep bruxism [40, 41]. Sleep related leg cramps are common. Almost all adults have had a leg cramp during sleep, and likely during wakefulness. Nightly leg cramps are reported in 6% of adults older than 60 [42]. The precipitants of sleep related leg cramps are as numerous as the over-the-counter dietary supplements used to treat them. The fact that no supplement has dominated the market speaks to their success. Predisposing factors include, but are not limited to, hypokalemia, hypocalcemia, hypomagnesemia, vigorous exercise, prolonged standing, oral contraceptives, diuretics, and long duration of action beta blockers [43]. Prescription medications including carisoprodol, diltiazem, gabapentin, orphenadrine, verapamil, have been used with success that likely does not significantly exceed placebo, presuming there were any controlled trials.
3.1 Periodic limb movement disorder/restless leg syndrome
The remaining sleep related movement disorders are the closely related periodic limb movement disorder and restless leg syndrome. Restless leg syndrome (RLS) is a clinical symptom complex. Periodic limb movements (PLM) are a polysomnographic finding seen very frequently with the symptom complex of restless leg syndrome. When the symptom complex of restless leg syndrome is absent, the polysomnographic finding of periodic limb movements become a disorder when there is clinically significant sleep disturbance or impairment in mental, physical, social, occupational, educational, behavioral, or other areas of functioning [2]. Periodic limb movements are seen on polysomnograms with greater frequency as patients grow older, though not all of these patients complain of sleep disturbance or nonrestorative sleep. Patients with periodic limb movement disorder can develop symptom worsening with prescription drugs including selective serotonin reuptake inhibitors, tricyclic antidepressants, lithium, and dopamine receptor antagonists. Low brain iron levels as manifested in peripheral blood by low ferritin levels and low total iron binding percentage are another precipitant. As with RLS, gene variants have been identified accounting for a fraction of affected individuals with a family history [3]. Care must be taken on polysomnograms to separate arousals secondary to limb movements from arousals due to sleep related breathing disorders. Distinction of periodic limb movements of sleep with no secondary sleep arousal versus periodic limb movement disorder with secondary arousal can be difficult. This is especially true of patients undergoing polysomnograms for another sleep pathology, such as suspected sleep related breathing disorder. The use of PLM associated cortical electroencephalographic arousals to determine clinical significance of periodic limb movements may thus be misleading. Cortical arousals as measured by an abrupt change to 3 seconds of 8 cycles per second rhythms (or higher frequencies) within 0.5 second of the limb movement [44] may be more subjective than the rule would suggest. Thus, the decision to treat or not to treat a patient with a periodic limb movement index of greater than 15 limb movements per hour can be dependent on the treating physician’s overall clinical assessment. Restless leg syndrome is an urge to move the legs usually accompanied by an uncomfortable sensation in the legs. The need to move worsens with rest, is relieved by movement, and emerges in a drug naïve patient at a specific time in their circadian cycle, usually in the evening [2]. Between 21 and 57% of patients will have arm symptoms. Sleep initiation and maintenance may be quite difficult for these patients resulting in their seeking medical care. The overall prevalence of RLS is estimated to be 5–10% in Europe and the United States but lower in Asia. Both prevalence and severity increase with age. Family history (obtained in 40–92% of cases) and the female gender confer increased risk. Pregnancy, especially the third trimester, has a risk three times greater risk than the general population. Restless leg syndrome is a clinical diagnosis that requires differentiation from the pain of leg cramps, arthralgias, myalgias, neuropathic pain, neuroleptic-induced akathisia, subtle spasticity from myelopathy, and anxiety-induced restlessness and repetitive movements. Many of these patients require prescription medications for control of symptoms. Medications for RLS and PLM disorder fall into four classes which will be discussed in depth later in this chapter. The four classes are the dopamine agonists, the alpha 2 delta subunit neuronal voltage-gated calcium channel blockers, the benzodiazepines and the opioids.
4. Implications for pharmacological management
The prescription drugs used in parasomnias and sleep related movement disorders fall into several classes. The benzodiazepines are broadly used for parasomnias and sleep related movement disorders. Melatonin is also widely used for parasomnias. Antidepressants with various pharmacodynamic properties are often used both to suppress parasomnias and treat comorbid mood disorders. Prazosin is a drug that has been widely used for nightmares. The dopamine receptor agonists are used with great frequency for both periodic limb movements and restless legs syndrome. The alpha 2 delta subunit neuronal voltage-gated calcium channel blockers are used predominantly for RLS/PLMD and other disorders. The final class of prescription drugs is the opioids.
We cannot go further into this chapter without taking into consideration the ideal properties of a drug to treat sleep disorders. These properties of oral medications include good gastro-duodenal absorption, ability to cross the blood brain barrier, a metabolic rate and duration of action that match the need for intervention, and a low potential for drug interactions. Low short-term and long-term effects on the molecular receptor target are also important. Direct and indirect adverse effects are additional determinants of patient compliance and satisfaction.
5. The Benzodiazapines
The benzodiazepines were first synthesized by Leo Sternbach in 1955 [45]. The benzodiazepines had activity on the neuronal chloride ionophore augmenting the effect of gamma aminobutyric acid (GABA) in facilitating sleep, sedation, anti-anxiety effects, and muscle relaxation. Hundreds of benzodiazepines were synthesized between 1960 and 1980 [46], but only a few have had commercial success. With the marketing of chlordiazepoxide in 1960 and diazepam in 1963 the benzodiazepines increased rapidly in prescription frequency [47]. The utility of these drugs as anti-anxiety agents and sedative hypnotics was important to this rise, but safety characteristics were equally important. The therapeutic window of the benzodiazepines was much wider than the barbiturates and the lethal dose for 50% of animals in toxicology studies of diazepam was ten times that of secobarbital [48]. Over 50 years the growth of benzodiazepine prescribing was substantial. In 2017 there were 45.0 million alprazolam, 26.4 million lorazepam, 29.2 million clonazepam, 12.6 million diazepam, and 7.0 million temazepam prescriptions dispensed in the United States [49]. The benzodiazepines were placed in Schedule IV of the Controlled Substances Act of 1971. Alprazolam was one of the top three prescription drugs diverted to the illicit market. While the benzodiazepines were less dangerous than barbiturates due to a wider therapeutic window, there were still 14 deaths associated with benzodiazepines in 2017, most due to intentional overdose. According to the National Institute on Drug Abuse there were a total of 70,630 overdose deaths in the United States in 2019 [50]. Most of those deaths were due to opioids, mainly fentanyl. The benzodiazepines were involved in 9,711 of those deaths, usually in combination with opioids. By comparison there were 5,175 deaths in 2019 associated with antidepressants. Many dose-related adverse effects of benzodiazepines resulted from depression of the central nervous system including drowsiness, impaired judgment, diminished motor skills, and anterograde amnesia, causing falls and confusion in the elderly, breathing problems in symptomatic sleep apnea or chronic pulmonary disease, driving impairment, and worsened job performance.
5.1 Pharmacokinetics and pharmacodynamics
The GABA system is the location of the primary pharmacodynamics of the benzodiazepines [51]. This system is the major inhibitory system in the central nervous system, thus the drug effect producing central nervous system depression. The GABA-A receptors upon which the benzodiazepines produce their effect are pentameric ligand-gated chloride ion channels. There are 21 different subunit isoforms within the GABA-A chloride ionophore. These are divided into eight families which within their family share 70% of their amino acid sequences. These subunit families are classified into alpha, beta, gamma, delta, epsilon, pi, omega, and rho. The first four of these are most important for benzodiazepine action. The structure most frequently seen in the brain consists of two alpha subunits and two beta subunits and one gamma or, less frequently, one delta subunit [52]. The neurotransmitter GABA binds to the interface between the alpha and beta subunits to open the chloride ionophore. Benzodiazepines bind to the interface of the alpha and gamma subunits. The benzodiazepine binding produces an allosteric change making the GABA receptor more sensitive, producing benzodiazepine clinical effects. Of interest for future drug development, the alpha subunit family contains alpha-1 through alpha-6 subunits which vary in benzodiazepine sensitivities and specific clinical effects [53, 54]. Thus, alpha subunit composition containing alpha-1 is associated with sedation, amnesia, anti-seizure activity, and addiction propensity. Alpha-2 subunits are associated with anti-anxiety propensity, muscle relaxation, cognitive disturbance, and analgesic properties. Alpha-5 subunits are associated with learning, memory, and muscle relaxation.
While the basic 3 ring skeletal molecular structure of the benzodiazepines is the same, different additions to this molecular structure yield important differences in properties. Classification of these additions to the basic benzodiazepine nucleus use 7 groupings, five of which are important to this discussion. The triazolo group (alprazolam, triazolam, estazolam) and the imidazo group (midazolam) include drugs that are closely related structurally. Likewise, the 3-hydroxy group (lorazepam, oxazepam, and temazepam) all have similar molecular structures. The 2-keto group, including diazepam and the 7-nitro group including clonazepam are significantly different structurally from the other benzodiazepines. These molecular structure differences contribute to the pharmacologic properties of these drugs. The GABA-A receptors also change in response to exogenous factors including benzodiazepine exposure. Internalization of the receptor complex leads to degradation and altered composition of the pentameric structure, rendering the receptor complex less sensitive and less numerous.
There are two prime factors in the choice of a benzodiazepine, half-life and potency. A low potency and long half-life benzodiazepine is diazepam and a low potency and short half-life benzodiazepine is temazepam. A high potency and long half-life benzodiazepine is clonazepam and two high potency short half-life benzodiazepines are alprazolam and lorazepam. The pharmacodynamic effects of the benzodiazepines are similar. Thus, pharmacokinetic properties, potency, dosing requirements, and efficacy have determined usage. Several of the benzodiazepines have been used in the pharmacologic treatment of parasomnias and sleep related movement disorders, and as a class may be the most frequent and widely used pharmacological management. Four commonly used agents are described below in alphabetical order.
5.2 Alprazolam
This triazolo benzodiazepine was approved by the FDA in 1981 for the treatment of panic disorder. The doses of alprazolam for panic disorder were very high, up to 6–12 mg per day. It quickly became the most widely prescribed benzodiazepine shortly after marketing. The oral absorption of alprazolam after a single 1 mg dose is rapid with an oral bioavailability of 80–100% and peak plasma concentrations in young males occurring within 0.7 to 1.8 hours after administration [55]. It is a CYP3A4 substrate subject to multiple metabolic inducers and inhibitors. The metabolic products of hepatic microsomal oxidation yield alpha-hydroxy and 4-hydroxy alprazolam which have 10% of the plasma concentrations of the parent drug and lower affinity for benzodiazepine receptors. A number of drugs may impair metabolism of alprazolam, including fluoxetine [56] and propoxyphene, enhancing central nervous system effects. The elimination half-life in young men ranged from 9 to 16 hours. Healthy elderly men had significantly longer half-lives with a mean of 19 hours versus a mean of 11 hours in young men [57].
Alprazolam falls into the intermediate range among benzodiazepines in regards to lipid solubility (50% of diazepam). This characteristic determines the degree of uptake into the brain [58] as well as the speed at which alprazolam enters the brain. Several studies have demonstrated that the steady state plasma concentrations of alprazolam after multiple dosing are proportional to the daily dose and do not change the half-life [59, 60, 61].
The general binding characteristics are similar to the other benzodiazepines, however, the receptor affinity of alprazolam (Ki) of 3.4 nm is tighter than diazepam’s Ki of 5.3 nm [62]. This reflects the potency enhancement from the chloride at position 8 on the phenyl ring along with the triazolo ring. This enhancement is even tighter for another triazolobenzodiazepine, triazolam, with its remarkable receptor affinity (Ki) of 0.5 nm [63]. A unique characteristic not shared by other benzodiazepines [62] was seen with low doses (0.02–0.05 mg/kg) of alprazolam in mice [64]. An increased benzodiazepine receptor number was seen compared to the decreased receptor number seen with other benzodiazepines and high dose alprazolam.
Clinical information regarding the use of alprazolam in REM sleep behavioral disorder is limited [65]. Published results [66, 67] yield varying utility, though this author’s results [68, 69] have been quite positive at doses of alprazolam 0.5 mg at bedtime. Alprazolam would appear to have good pharmacokinetic and pharmacodynamic properties for use in nocturnal parasomnias when a benzodiazepine is indicated. Currently, however, it is not frequently prescribed for that purpose. Of note, in the elderly (>65 years old) there is a significant and dramatic dose related increase in sedation and neuromotor testing decrement between alprazolam doses of 0.5 mg and 2.0 mg [60].
5.3 Clonazepam
Clonazepam is the most common drug used for parasomnias. It is limited to oral administration, but has been used widely for panic disorder and psychosis, as well as, having anti-seizure properties shared with diazepam, lorazepam, and clobazam. This 7-nitro group benzodiazepine differs structurally from other benzodiazepines resulting in high potency and tight binding affinity (Ki 2.0 nm) to benzodiazepine receptors. Clonazepam is rapidly and completely absorbed after oral administration and reaches peak plasma concentrations in 1–4 hours [70]. Absolute bioavailability is 90%. It is highly metabolized by the hepatic microsomal system with less than 2% being excreted unchanged in the urine. The remarkable property of this drug is its long half-life of 30–40 hours. The constant presence of the drug with multiple dosing results in benzodiazepine downregulation with loss of both high affinity binding and receptor number [71, 72]. Specific clonazepam binding was reduced by 24.9% with chronic administration. This likely explains the loss of efficacy and development of tolerance with multiple dosing. Clonazepam, more than lorazepam or alprazolam, produced impairment on neuromotor tasks [73, 74]. Alprazolam showed significantly faster recovery on testing performance than either clonazepam or lorazepam even though lorazepam has a similar half-life. Ellinwood et al. also found that the equivalent dose of alprazolam was half the dosage level of the other two drugs, a phenomenon that could not be explained by receptor affinity. The length of impairment with lorazepam was greater than clonazepam presumably secondary to its greater lipid solubility.
Clonazepam is currently the suggested treatment for REM sleep behavioral disorder with more published studies than other drugs that have been used in this disorder [65]. Clonazepam showed efficacy in 80% of 200 patients at the Minnesota Regional Sleep Disorders Center [66, 67]. There is concern, however, for the use of clonazepam in dementia, gait disorders, and obstructive sleep apnea due to reports of worsening of each of these with chronic clonazepam dosing. Aurora et al. [65] reviewed the adverse event profile of clonazepam and found reports of sedation, impotence, early morning loss of motor coordination, confusion, and memory dysfunction.
5.4 Diazepam
Diazepam, within six years of it being marketed, became the most prescribed drug in the United States from 1969 to 1982 [49]. Diazepam has chemical properties of lipid solubility and non-ionization at physiological pH that made absorption through the gut wall and cerebral capillaries rapid, allowing potent brain concentrations within minutes. Peak blood levels with oral dosing are achieved in 1–2 hours. The half-life varies between 20 and 80 hours making the drug a long-acting agent. Diazepam gained multiple uses including anti-anxiety, sedative, anti-seizure, anti-vertigo, and muscle relaxant effects due to its action on both central and peripheral benzodiazepine receptors. It is available in oral, rectal, and parenteral formulations. Hepatic metabolism of diazepam produces an active metabolite, desmethyldiazepam (DMD), which at steady state with repeated dosing eventually has a higher plasma concentration than its parent drug. The elimination of DMD occurs much more slowly than diazepam with a half-life of 36–96 hours. If diazepam is discontinued, withdrawal symptoms can occur ranging from anxiety to seizures with higher doses. Diazepam remains a secondary benzodiazepine for both non-REM and REM sleep related parasomnias. It is a tertiary treatment when first and second-line treatments have failed.
5.5 Lorazepam
Lorazepam has many uses in addition to its indication for anxiety with depression. It has been used as a hypnotic and as a treatment for panic disorder, alcoholic delirium tremens, status epilepticus, and pre-procedural sedation [73]. It is available in oral and parenteral formulations. Its use for parasomnias and sleep-related movement disorders has been limited and Aurora et al. [65] did not report lorazepam being used for REM sleep behavior disorder.
Lorazepam is one of the 3-hydroxy group of benzodiazepines. This drug is available in oral and parenteral formulations and is metabolized by glucuronidation thus the absence of concern for hepatic impairment or an active metabolite. It has utility for anti- anxiety and anti-seizure applications. It is absorbed quickly after oral administration with a time to peak plasma levels of 1–5 hours [70]. Like diazepam, lorazepam is highly lipophilic and quickly crosses the blood–brain barrier. It is rapidly absorbed when administered orally and has a half-life of 10–20 hours. As discussed in Section 4.1b, lorazepam has a longer duration of action than might be expected for its elimination half-life. The ortho chloride on the ring structures of lorazepam, clonazepam, and triazolam increase receptor binding and thus potency. The tighter binding may be the reason for the longer duration of action [73].
6. Melatonin
Endogenous melatonin is a hormone secreted by the pineal gland in tandem with the circadian rhythm. Studies of melatonin revealed sedative properties leading to its use in sleep disorders [75, 76, 77]. Melatonin is considered a dietary supplement by the Food and Drug Administration in the United States and thus the formulations are not subject to the regulations that govern prescription medications mentioned in this chapter.
Buscemi et al. [78] did a clinical review of 14 randomized controlled trials of exogenous melatonin for sleep disorders. The meta-analysis showed a reduced sleep latency of 11.7 minutes (CI: −18.2, −5.2), but this was most significant in those patients with delayed sleep-phase syndrome. All of the patients studied carried diagnoses of either insomnia or delayed sleep-phase disorder. No doses higher than 5 mg per night were used and half the studies used no more than 3 mg per night. Of the 222 combined participants, 13 reported headaches, 10 dizziness, 3 nausea, and 3 drowsiness. In all of these there was no significant difference between melatonin and placebo.
Moroni et al. [79] conducted another systematic review looking at 19 published studies utilizing different formulations of exogenous melatonin. Most of the studies reviewed used low dose melatonin (<5 mg). The immediate-release formulations produced a decrease in sleep onset latency and the sustained release formulations had a greater effect on reducing wakefulness after sleep onset. Oral formulations of melatonin had variability in both absorption and metabolism. There were no adverse effects noted in very short-term therapy among healthy research participants.
The amount of melatonin that enters the systemic circulation is decreased by first-pass metabolism. The hepatic enzyme involved in metabolism of melatonin is CYP1A2 [80, 81]. This enzyme has higher activity in males, likely contributing to the gender differences seen in one study [82] which showed almost three times higher systemic circulation concentrations in females. An older group of research participants also showed three times the maximal concentration in their systemic circulation [83].
The Standards of Practice Committee of the American Academy of Sleep Medicine (AASM) published recommendations which included a suggestion that melatonin be used for the treatment of REM sleep behavior disorder [65]. They noted that melatonin had been shown to be effective with few adverse effects. There are actually only a few reports showing efficacy of melatonin in parasomnias [75, 84]. This author’s experience in a large university sleep clinic confirms the efficacy of melatonin in some patients, but the patients with parasomnias treated successfully with melatonin comprise less than half of the patients treated successfully with benzodiazepines [68].
Dose related adverse effects were reported including headache, morning sleepiness, and delusions/hallucinations [75]. In another set of AASM recommendations for the management of circadian disorders [85] melatonin adverse effects were discussed in greater depth. There were no serious adverse effects, however, headaches, somnolence, hypotension, hypertension, gastrointestinal upset, and exacerbation of alopecia areata were all reported. An increase in depressive symptoms [86], impairment of glucose tolerance [87], and reproductive function [88] were reported. Studies beyond 3 months of melatonin use and studies in pediatrics were and remain scarce. Pediatric concerns were reported including potential effects on growth hormone regulation with high dose melatonin (10 mg) [89]. There was additional thought that the efficacy in pediatric parasomnias might be related to an indirect effect of improving sleep rather than a direct effect of melatonin [65].
In conclusion, melatonin is efficacious in some patients with REM sleep behavioral disorder and possibly other parasomnias with no serious adverse effects.
7. The antidepressants
There have been many antidepressants used in patients with a variety of parasomnias either as primary or concomitant therapy. Parasomnias can be co-morbid with mental health disorders leading to antidepressant treatment. The confounding factor is that some parasomnias and sleep-related movement disorders may be exacerbated or even elicited by antidepressant therapy [90, 91, 92, 93, 94]. Lam et al. [95] used a questionnaire to identify patients with parasomnias then confirmed the diagnosis via a clinical interview. Of the 1235 participants who completed the interview 22.3% had clinically confirmed somnambulism, sleep-related eating disorder, or sleep related injury. REM sleep behavior disorder (RSBD) was the cause of sleep related injury in 66.7% of the subgroup of participants with sleep related injury. The use of selective serotonin reuptake inhibitors (SSRIs) was associated with symptoms of RSBD in 5% of participants. Of the 29 participants diagnosed with somnambulism 34.5% were using sedating antidepressants [96].
Drug-induced RSBD has been further associated with the tricyclic antidepressant clomipramine and the monoamine oxidase inhibitors selegiline and phenelzine [94]. In spite of these risks co-morbid psychiatric disorders often lead to treatment with antidepressants in individuals with parasomnias. There are also a variety of case reports of the effective use of antidepressants for management of parasomnias. Imipramine was used successfully in seven children diagnosed with sleep terrors or somnambulism [97]. Paroxetine at a dose of 40 mg in the morning was used successfully in a 46-year-old woman with a 30-year history of sleep terrors and somnambulism. REM suppressant properties of the antidepressants would appear to be a rational approach to the control of nightmares, though the evidence is not convincing [98]. Given these therapeutic uncertainties with use of the antidepressants for parasomnias and sleep related movement disorders, these drug classes are not first line treatments for these disorders and will not be discussed in depth here.
The two drugs in this class are gabapentin and pregabalin and will be discussed separately. These drugs are not used for management of parasomnias, but have gained increasing favor for use in restless legs syndrome and periodic limb movement disorder. The current recommendations of the Scientific and Medical Advisory Board of the Restless Legs Syndrome Foundation were recently published in Mayo Clinic Proceedings. The alpha 2 delta subunit neuronal voltage-gated calcium channel blockers were recommended as first line therapy for chronic persistent restless legs syndrome (RLS) [99].
8.1 Gabapentin
Gabapentin was approved in December 1993 by the Food and Drug Administration (FDA) for the adjunctive therapy of partial seizures. After initial approval gabapentin sales increased significantly due to off-label uses for treatment of chronic pain syndromes [100]. In 2000 gabapentin was the top-selling anticonvulsant and ranked 17th in total expenditures among all drugs. In 2002 the FDA added the indication of postherpetic neuralgia, but by 2004 gabapentin sales had increased to 3 billion dollars per year [101]. In 2004 the US Department of Justice issued its largest fine to date ($430 million) to the Warner-Lambert group of pharmaceutical companies, manufacturer of gabapentin, for promoting gabapentin for uses not approved by the FDA [102]. In 2012 gabapentin enacarbil (a pro-drug with better absorption characteristics) received FDA approval for the treatment of restless legs syndrome and postherpetic neuralgia. By 2015 the use of gabapentin formulations had tripled from 2002 [103]. In 2017 gabapentin was the fifth most commonly prescribed medication in the United States [104].
Gabapentin has many desirable pharmacokinetic properties [105]. Mean maximum plasma concentrations were attained 2–3 hours after a 300–400 mg oral dose with a bioavailability of 60%, however, absorption kinetics are slowed and bioavailability decreased as the dose is increased. Gabapentin readily crosses the blood brain barrier due to its lipid solubility. It is not bound to plasma proteins. The elimination half-life is dependent on renal clearance alone in a linear fashion. The drug does not affect the metabolism of other drugs or induce hepatic enzymes. The elimination half-life of gabapentin after a single oral dose of 200–400 mg is about 5–7 hours with 80% of the dose recoverable unchanged in the urine. The most common adverse effects (significantly greater than placebo) are somnolence, dizziness, and ataxia. Happe et al. [106] reported efficacy of gabapentin given 2 hours before bedtime in restless legs syndrome in 2001. Subsequently, gabapentin enacarbil was found to be effective in a double-blind, placebo-controlled, multicenter study of 325 subjects [107]. This pro-drug (rapidly converted to gabapentin after absorption) sought to overcome the absorption deficiencies of gabapentin which was dependent upon active transport by a low-capacity nutrient transport system expressed in a narrow region of the upper small intestine. Gabapentin enacarbil is actively transported by a high-capacity nutrient transporter located throughout the large and small intestine [108]. There was significant improvement in RLS symptoms with both the 600 mg and 1200 mg doses of gabapentin enacarbil in the 12-week study compared to placebo. The most commonly reported adverse effects were dizziness and somnolence. Gabapentin enacarbil remains a preferable drug to generic gabapentin, however, cost concerns have made generic gabapentin more widely prescribed.
8.2 Pregabalin
Pregabalin and gabapentin share the same mechanism of action, inhibiting calcium influx into neuronal terminals and thus inhibiting the release of excitatory neurotransmitters. Orally dosed pregabalin is absorbed more rapidly than gabapentin with maximal plasma concentrations achieved in 1 hour [108]. The absorption is linear with plasma concentrations increasing proportionally to dose and the bioavailability of 90% or greater. Neither drug binds to plasma proteins or inhibits hepatic enzymes, and both drugs are eliminated by renal excretion alone with elimination half-lives of less than 6 hours. At higher dose therapy (1800–4800 mg) gabapentin bioavailability can fall to 25–50% [109]. Pregabalin bioavailability remained above 90% across its entire dose range.
A randomized, double-blind, 6-week study of pregabalin in 137 patients with restless legs syndrome showed an effective daily dose for 50% of patients at 37.3 mg and for 90% of patients at 123.9 mg per day [110]. A higher proportion of responders to the Clinical Global Impressions-Improvement Scale (CGI-I) was seen at the two highest doses of pregabalin 300 and 450 mg per day. Dizziness and somnolence were the most common adverse effects, though dry mouth complaints also exceeded placebo. A second double-blind, placebo-controlled study [111] was performed almost simultaneously with the Allen et al. [110] study. This second study randomized 58 patients in a 12-week flexible-dose trial. The mean effective dose at the end of treatment was 322.5 mg per day. There was a significant improvement in the International Restless Legs Scale (IRLS) and Clinical Global Impression (CGI). Polysomnography measured a reduction in mean periodic limb movement index, improvement in sleep architecture, and decrease in wakefulness after sleep onset. Adverse effects were reported to be mild and included unsteadiness, somnolence, and headache.
From the earliest studies of pregabalin there has been a concern about cognitive effects of this drug. Salinsky et al. [112] looked at this potential adverse effect in 32 healthy volunteers. The participants were randomized in a double-blind, parallel study receiving either pregabalin or placebo. Pregabalin was titrated over 8 weeks to 600 mg per day. At baseline and after 12 weeks of treatment all subjects underwent cognitive testing. A battery of 14 tests were used including finger tapping, grooved pegboard, digit symbol, Stroop color-word, selective reminding, name learning, story recall, Wonderlic personnel, visual reaction time, controlled oral word association, divided attention, letter-number sequencing, profile of mood states and Portland neurotoxicity scale. Thirty subjects completed the trial. There was significant (p < 0.01) worsening in the treatment group on the objective Stroop-color-word test and controlled oral word association test, as well as, the subjective Portland neurotoxicity scale. While the study demonstrated cognitive effects, both the speed of the titration and the final dose were greater than this author’s current practice and the methodology of the treatment studies described here. This study, however, does demonstrate concerns over rapid dose increases and high dose therapy.
9. The dopamine receptor agonists
The dopamine agonists have been the first line treatment of periodic limb movement disorder and restless legs syndrome for many years. It is only recently that the alpha 2 delta subunit neuronal voltage-gated calcium channel blockers have advanced to preferred therapy [99]. It has, however, been long appreciated that the dopamine receptor agonists have adverse effects [113]. Impulse control disorders such as pathological gambling, hypersexuality, compulsive shopping, or an irresistible urge to wander have been identified in surveys [114]. The D3 dopamine receptor has been implicated in these behaviors [115], however, no dose response curve or dose related risk assessment has been established for these phenomena. A more pervasive and widespread adverse effect is the phenomena of augmentation. Augmentation manifests as earlier onset of RLS symptoms with decreased duration of benefit from medications and symptoms involving other parts of the body. Though the highest risk of augmentation occurs with short acting agents such as levodopa, current expert opinion is that augmentation will occur with all the currently available dopamine agonists over time [99].
9.1 Pramipexole
Pramipexole is a non-ergot dopamine agonist with higher affinity to D3 than D2 or D4 receptor subtypes. It has FDA indications for Parkinson’s disease and restless leg syndrome [116]. It is rapidly absorbed and reaches peak plasma concentrations in 2 hours. If taken with a meal the absorption is delayed by about an hour. The bioavailability of pramipexole is greater than 90%. Renal excretion is the primary route of elimination with 90% of the dose recovered unchanged in the urine. The half-life of pramipexole is 8 hours in young adults and 12 hours in the elderly. The most common adverse effect (in excess of placebo) was somnolence. The recommended final treatment dose after up-titration was 0.5 mg given 2–3 hours before bedtime. Though higher doses are used in practice, the risk of increasing augmentation with high dose therapy leads to concern about high dosing [68].
9.2 Rotigotine
Rotigotine is dispensed as a transdermal delivery system [117]. It is a non-ergoline dopamine agonist for the D3, D2, and D1 dopamine receptors approved by the FDA for use in RLS as well as Parkinson’s disease. When a patch is applied there is a 3-hour delay before the drug is detected in plasma and the time to maximal plasm levels is 15–18 hours. Approximately 45% of the dose is released from the patch in 24 hours. After removal of the patch the elimination half-life is 5–7 hours. Most rotigotine is eliminated in the urine as inactive conjugates. The highest recommended dose (for RLS) of rotigotine is 3 mg per 24 hours. The most common adverse effect was a skin reaction at the site of the patch, though nausea also exceeded placebo. The constant delivery system suppresses RLS augmentation temporarily though other medications may ultimately be needed for breakthrough symptoms [68].
9.3 Ropinirole
Ropinirole is a selective non-ergoline dopamine D3 much greater than D2 receptor agonist [118]. It is rapidly absorbed but its bioavailability is only 50%. The maximal plasma concentrations are achieved in 0.5 to 4 hours (mean 1.5 hours). The drug is metabolized in the liver to inactive metabolites by the P450 iso-enzyme CYP1A2. The elimination half-life is 3 hours, though this can be variable and elderly patients have 15% slower clearance. The drug is FDA approved for use in restless legs syndrome, as well as, Parkinson’s disease. The short half-life and duration of action of this drug can lead to tachyphylaxis and doses higher than recommended producing a high rate of augmentation in the author’s experience.
10. Prazosin
The American Academy of Sleep Medicine published a position paper on the treatment of nightmare disorder in 2018 [119]. The position paper divided nightmares into those associated with post-traumatic stress disorder (PTSD) and those not associated with PTSD. Nightmares associated with PTSD are more difficult to suppress and thus a wide variety of behavioral and drug combinations have been used, beyond the capability of this chapter. The drugs that may be used in nightmare disorder in the absence of PTSD are benzodiazepines, not including clonazepam, and prazosin.
Prazosin is a quinazoline derivative and peripheral vasodilator [120]. Its vasodilator properties are due to postsynaptic alpha adrenergic receptor blockade. Prazosin is extensively metabolized in the liver producing high first pass elimination and resultant low oral bioavailability after oral dosing. With an oral dose of 1 mg in normal subjects the bioavailability of prazosin ranged from 43.5 to 69.3% [121]. The mean elimination half-life is about 2.5 hours. Prazosin shows initial dose postural hypotension which disappears with continued administration.
On acute administration of prazosin, only very low levels crossed the blood–brain barrier [122]. On chronic administration of high dose prazosin, however, prazosin apparently crossed the blood–brain barrier in adequate concentrations to affect the central alpha adrenergic receptor density in the cerebral cortex [123]. This effect would not have occurred without significant penetration of prazosin into the brain. There were a number of studies showing efficacy of prazosin in veterans with PTSD induced nightmares [119]. In contrast, however, there was a recent large randomized, placebo-controlled study with negative results [124], leading to uncertainty about this treatment.
11. The opioids
Various opioids have been used for intractable restless legs syndrome. These include propoxyphene [125]. tramadol [126], oxycodone [127], hydrocodone [128], and methadone [129]. Most of these have been used as adjunctive therapy, but methadone has been used in monotherapy. The mechanism of action of the opioids in RLS is unclear, however, it appears to work through a central dopaminergic neurotransmission as dopamine receptor antagonists will block the therapeutic effect. The current opioid crisis has lent a stigma to chronic use of methadone that has discouraged its use by many patients suffering with intractable restless legs syndrome. This is unfortunate as opioid therapy with management directed towards restless legs syndrome rather than chronic pain syndromes can be quite helpful [130]. The concern with long-term opioid therapy is the occult development or exacerbation of a sleep related breathing disorder. For this reason, all patients on chronic opioids should be clinically monitored for evidence of sleep apnea [131].
11.1 Methadone
Methadone is a synthetic opioid that is nearly equipotent with morphine, but with dramatically different pharmacokinetic characteristics [132]. Methadone is a racemic mixture of R and S-methadone with the R isomer being 8–50 times more potent. Methadone may prevent or attenuate opioid tolerance via its weak antagonist properties on the N-methyl-D-aspartate (NMDA) receptor. Methadone is rapidly absorbed with maximal plasma concentrations 2.5 to 4 hours after oral administration. The bioavailability of methadone is 70–80%, though this can vary depending on the degree of first pass metabolism. Methadone is hepatically metabolized to inactive metabolites by the cytochrome P450 enzymes, CYP3A4 and CYP2B6. The elimination half-life of methadone ranges from 5 to 130 hours with a mean of 20–35 hours. The elimination half-life of the R isomer is approximately 25% longer than the S isomer. Methadone shows apparent autoinduction of its own metabolism. The half-life during chronic therapy is only 40% of the half-life with acute administration. A number of medications can either decrease or increase methadone levels via induction or inhibition of CYP3A4. Quantitative plasma levels may be necessary. Of note, there have been unintentional deaths with methadone. Many of these deaths occurred on the fifth day of regular dosing [133]. Prescribers need to be aware of methadone’s peculiar pharmacokinetics.
In practice doses of methadone from 5–40 mg daily have been used. Given the pharmacokinetics starting therapy at a small dose of 2.5–5 mg is appropriate with up-titration of the dose as needed for symptoms. Methadone in patients with intractable RLS can produce remarkable improvement [68, 129].
11.2 Oxycodone-naloxone
Constipation and bowel dysfunction is the prime adverse effect of long-term opiate therapy. The combination of an opioid with a competitive mu receptor antagonist in a sustained release formulation is a unique answer to opioid adverse effects. The combination is also a tool against abuse of oxycodone since dissolution and injection results in naloxone having a much greater effect blocking mu receptors. A double-blind, randomized, placebo-controlled trial with this formulation was performed with 276 RLS patients [134]. The study started participants on a dose of oxycodone 5.0 mg and naloxone 2.5 mg twice a day increasing per each study site’s investigator to a maximal dose of oxycodone 40 mg and naloxone 20 mg. Adverse effects more than twice as frequent as placebo included fatigue, constipation, somnolence, dry mouth and pruritis. There was clear efficacy of the combination over placebo.
12. Conclusions
This chapter did not attempt to be all inclusive, as a full description of the pharmacological interventions into sleep related movement disorders and parasomnias would fill the entire book. The chapter does attempt to provide pharmacological basis for treatment of the most challenging areas for pharmaceutical intervention, notably the REM sleep parasomnias and restless legs syndrome.
A challenge of REM sleep parasomnia management is the continuing use of clonazepam as first line therapy. This potent drug is effective, but due to its extremely long half-life, is prone to adverse effects in many patients. Unfortunately, the even more potent drug, triazolam, is too short acting and the two drugs (alprazolam and lorazepam) with duration of actions that are reasonable for the goal of suppressing dream enactment are less potent than either triazolam or clonazepam, thus appearing to need higher doses. Unexpectedly, the observational experience of the University of Texas Southwestern Medical Center at Dallas Clinical Center for Sleep and Breathing Disorders has been that the efficacy of alprazolam is half the expected dose that was used in trials in Minneapolis. Retrospective review is in progress.
The other pharmacological challenge is the management of severe persistent and intractable restless leg syndrome. In recent decades the algorithms for management have become clearer pointing to the early use of gabapentin and pregabalin and the use of opioids in intractable patients, however, there is a lag of that knowledge reaching the medical community that is faced with these patients and their demands for treatment. This is another area where the growth of medical knowledge is exceeding our educational capabilities.
\n',keywords:"Treatment of parasomnias, movement disorders of sleep, pharmacology of sleep disorders, comparison of the benzodiazepines, comparison of the dopamine receptor agonists, gabapentin and pregabalin for sleep disorders, risks of sleep medications, melatonin, restless leg syndrome, alcohol, caffeine, and opiate effects on sleep disorders",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/78877.pdf",chapterXML:"https://mts.intechopen.com/source/xml/78877.xml",downloadPdfUrl:"/chapter/pdf-download/78877",previewPdfUrl:"/chapter/pdf-preview/78877",totalDownloads:163,totalViews:0,totalCrossrefCites:0,dateSubmitted:"August 18th 2021",dateReviewed:"September 15th 2021",datePrePublished:"October 7th 2021",datePublished:"January 7th 2022",dateFinished:"October 7th 2021",readingETA:"0",abstract:"The treatment of parasomnias and sleep related movement disorders is not always pharmacologic, indeed, some of these disorders respond to behavioral approaches without the risks of pharmaceuticals. This chapter endeavors to pull forward the disorders in which pharmacologic treatment is the best choice and lay out the pharmacologic properties of the treatments. It is not the goal of this chapter to present an encyclopedic review of the parasomnias and sleep related movement disorders. It is, however, the intent of this chapter to comprehensively review pharmacologic treatments used in the management of the disorders in which drug use is most necessary. The pharmacokinetic and pharmacodynamic properties and known risks of these pharmaceuticals are presented and discussed. When more than one pharmaceutical is used clinically within a class of drugs, thorough review of selected drugs is presented. The chapter includes investigations, mostly human studies, of the drugs discussed. The author’s extensive experience in pharmacology, neurology, and sleep medicine take the chapter through pharmacological information a clinician needs to guide the management of these disorders.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/78877",risUrl:"/chapter/ris/78877",signatures:"Gregory S. Carter",book:{id:"10350",type:"book",title:"Sleep Medicine and the Evolution of Contemporary Sleep Pharmacotherapy",subtitle:null,fullTitle:"Sleep Medicine and the Evolution of Contemporary Sleep Pharmacotherapy",slug:"sleep-medicine-and-the-evolution-of-contemporary-sleep-pharmacotherapy",publishedDate:"January 7th 2022",bookSignature:"Denis Larrivee",coverURL:"https://cdn.intechopen.com/books/images_new/10350.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",isbn:"978-1-83969-822-4",printIsbn:"978-1-83969-821-7",pdfIsbn:"978-1-83969-823-1",isAvailableForWebshopOrdering:!0,editors:[{id:"206412",title:"Prof.",name:"Denis",middleName:null,surname:"Larrivee",slug:"denis-larrivee",fullName:"Denis Larrivee"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"418748",title:"Dr.",name:"Gregory S.",middleName:"S",surname:"Carter",fullName:"Gregory S. Carter",slug:"gregory-s.-carter",email:"gregory.carter@utsouthwestern.edu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/418748/images/17211_n.jpg",institution:{name:"The University of Texas Southwestern Medical Center",institutionURL:null,country:{name:"United States of America"}}}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. The parasomnias",level:"1"},{id:"sec_2_2",title:"2.1 Clinical evaluation",level:"2"},{id:"sec_3_2",title:"2.2 Arousal disorders",level:"2"},{id:"sec_3_3",title:"2.2.1 Sleep-related Hypermotor epilepsy",level:"3"},{id:"sec_5_2",title:"2.3 REM parasomnias",level:"2"},{id:"sec_7",title:"3. Sleep related movement disorders",level:"1"},{id:"sec_7_2",title:"3.1 Periodic limb movement disorder/restless leg syndrome",level:"2"},{id:"sec_9",title:"4. Implications for pharmacological management",level:"1"},{id:"sec_10",title:"5. The Benzodiazapines",level:"1"},{id:"sec_10_2",title:"5.1 Pharmacokinetics and pharmacodynamics",level:"2"},{id:"sec_11_2",title:"5.2 Alprazolam",level:"2"},{id:"sec_12_2",title:"5.3 Clonazepam",level:"2"},{id:"sec_13_2",title:"5.4 Diazepam",level:"2"},{id:"sec_14_2",title:"5.5 Lorazepam",level:"2"},{id:"sec_16",title:"6. Melatonin",level:"1"},{id:"sec_17",title:"7. The antidepressants",level:"1"},{id:"sec_18",title:"8. The alpha 2 delta subunit neuronal voltage-gated calcium channel blockers",level:"1"},{id:"sec_18_2",title:"8.1 Gabapentin",level:"2"},{id:"sec_19_2",title:"8.2 Pregabalin",level:"2"},{id:"sec_21",title:"9. The dopamine receptor agonists",level:"1"},{id:"sec_21_2",title:"9.1 Pramipexole",level:"2"},{id:"sec_22_2",title:"9.2 Rotigotine",level:"2"},{id:"sec_23_2",title:"9.3 Ropinirole",level:"2"},{id:"sec_25",title:"10. Prazosin",level:"1"},{id:"sec_26",title:"11. The opioids",level:"1"},{id:"sec_26_2",title:"11.1 Methadone",level:"2"},{id:"sec_27_2",title:"11.2 Oxycodone-naloxone",level:"2"},{id:"sec_29",title:"12. Conclusions",level:"1"}],chapterReferences:[{id:"B1",body:'Roger H. Les Troubles du Sommeil. Paris: Masson; 1932 p. 275-283'},{id:"B2",body:'American Academy of Sleep Medicine. Parasomnias. In: AASM, ed. International Classification of Sleep Disorders, 3rd Edition. Darien: American Academy of Sleep Medicine; 2014. p. 225-280'},{id:"B3",body:'American Academy of Sleep Medicine. Sleep-related movement disorders. In: AASM, ed. International Classification of Sleep Disorders, 3rd Ed. Darien: American Academy of Sleep Medicine; 2014. p. 281-337'},{id:"B4",body:'Ohayon MM. Epidemiology of parasomnias. In: Thorpy MJ and Plazzi G, editors. Parasomnias and Other Sleep-Related Movement Disorders. New York: Cambridge University Press; 2010. p. 301-311'},{id:"B5",body:'Gulyani S, Salas RE, and Gamaldo CE. 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A double-blind, placebo-controlled study of the treatment of periodic limb movements in sleep using carbidopa/levodopa and propoxyphene. Sleep. 1993; 16:717-723'},{id:"B126",body:'Lauerma H and Markkula J. Treatment of restless legs syndrome with tramadol: An open study. J Clin Psychiatry. 1999; 60:241-244'},{id:"B127",body:'Walters AS, Wagner ML, Hening WA, Grasing K, Mills R, Chokoverty S and Kavey N. Successful treatment of the idiopathic restless legs syndrome in a randomized double-blind trial of oxycodone versus placebo. Sleep. 1993; 16:327-332'},{id:"B128",body:'Kavey N, Walters AS, Hening W, and Gidro-Frank S. Opioid treatment of periodic movements in sleep in patients without restless legs. Neuropeptides. 1988; 11:181-184'},{id:"B129",body:'Ondo WC. Methadone for refractory restless legs syndrome. Mov Disord. 2005; 20:345-348'},{id:"B130",body:'Becker PM. Opioid agents in the treatment of restless legs syndrome. In: Hening WA, Chokroverty S, Allen RP, and Earley CJ. Editors. Restless Legs Syndrome. Philadelphia: Saunders Elsevier; 2009. p. 255-261'},{id:"B131",body:'Walters AS, Winkelman J, Trenkwalder C, Fry JM, Kataria V, Wagner M, Sharma R, Hening W, and Li L. Long-term follow-up on restless legs syndrome patients treated with opioids. Mov Disord. 2001; 16:1105-1109'},{id:"B132",body:'Lugo RA, Satterfield KL, and Kern SE. Pharmacokinetics of methadone. Journal of Pain & Palliative Care Pharmacotherapy. 2005;19(4):13-24'},{id:"B133",body:'Caravati EM, Grey T, Nangle B, Rolfs RT, and Peterson-Porucznik. Increase in poisoning deaths caused by illicit drugs-Utah, 1991-2003. MMWR Morb Mortal Wkly Rep. 2005; 54(2):33-36'},{id:"B134",body:'Trenkwalder C, Benes H, Grote L, Garcia-Borreguero D, Hogl B, Bosse, B, Oksche A, Reimer K, Winkelmann J, Allen RP, and Kohnen R. Prolonged release oxycodone-naloxone for treatment of severe restless legs syndrome after failure of previous treatment: a double-blind, randomized, placebo-controlled trial with an open-label extension. Lancet Neurol. 2013; 12:1141-1150'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Gregory S. Carter",address:"gregory.carter@utsouthwestern.edu",affiliation:'
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Copyright is the term used to describe the rights related to the publication and distribution of original Works. Most importantly from a publisher's perspective, copyright governs how Authors, publishers and the general public can use, publish, and distribute publications.
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IntechOpen only publishes manuscripts for which it has publishing rights. This is governed by a publication agreement between the Author and IntechOpen. This agreement is accepted by the Author when the manuscript is submitted and deals with both the rights of the publisher and Author, as well as any obligations concerning a particular manuscript. However, in accepting this agreement, Authors continue to retain significant rights to use and share their publications.
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CW has been successfully applied as an adsorbent for removing pollutants from wastewater and gas, a precursor for obtaining activated carbon, and a feedstock for producing energy and valuable products using mono-process extraction and biorefinery.",book:{id:"8952",slug:"coffee-production-and-research",title:"Coffee",fullTitle:"Coffee - Production and Research"},signatures:"Felipe J. Cerino-Córdova, Nancy E. Dávila-Guzmán, Azucena M. García León, Jacob J. Salazar-Rabago and Eduardo Soto-Regalado",authors:null},{id:"56029",doi:"10.5772/intechopen.69614",title:"Production of Spineless Cactus in Brazilian Semiarid",slug:"production-of-spineless-cactus-in-brazilian-semiarid",totalDownloads:1905,totalCrossrefCites:4,totalDimensionsCites:8,abstract:"The term “spineless cactus” is used in Brazil to designate cultivars of Opuntia ficus indica Mill and Nopalea cochenillifera Salm Dyck. The spineless cactus was consolidated in Brazilian semiarid as a strategic fundamental food resource in several production livestock systems, constituting a plant with enormous productive potential. Thus, the spineless cactus has been widely cultivated and used for several decades, by enabling the animal feeding in critical periods of year because of its characteristics, morpho‐anatomical and physiological (CAM), which makes it tolerant to long droughts, being a crop that presents high productivity in droughts conditions, when compared to other forages. Nevertheless, the spineless cactus is a crop relatively picky about soil and climate characteristics of region, presenting greater growth in fertile soils, as well as in regions where nighttime temperatures are cool and the air humidity is relatively high. Although the crop be adapted to long droughts periods, many times it’s necessary to perform irrigation in its production system, mainly in regions of low rainfall, for to supply its water needs, thus ensuring productivity and survival of crop. Therefore, the knowledge of characteristics of plant, as well as of appropriate management techniques to crop, is essential for the good performance of spineless cactus.",book:{id:"5978",slug:"new-perspectives-in-forage-crops",title:"New Perspectives in Forage Crops",fullTitle:"New Perspectives in Forage Crops"},signatures:"Wilma Cristina Cavalcante dos Santos Sá, Edson Mauro Santos,\nJuliana Silva de Oliveira and Alexandre Fernandes Perazzo",authors:[{id:"139631",title:"Dr.",name:"Edson Mauro",middleName:null,surname:"Santos",slug:"edson-mauro-santos",fullName:"Edson Mauro Santos"},{id:"180036",title:"Dr.",name:"Juliana",middleName:null,surname:"Oliveira",slug:"juliana-oliveira",fullName:"Juliana Oliveira"},{id:"203022",title:"MSc.",name:"Wilma",middleName:null,surname:"Sá",slug:"wilma-sa",fullName:"Wilma Sá"},{id:"207265",title:"Dr.",name:"Alexandre",middleName:null,surname:"Perazzo",slug:"alexandre-perazzo",fullName:"Alexandre Perazzo"}]},{id:"70151",doi:"10.5772/intechopen.89224",title:"The Harvest and Post-Harvest Management Practices’ Impact on Coffee Quality",slug:"the-harvest-and-post-harvest-management-practices-impact-on-coffee-quality",totalDownloads:1868,totalCrossrefCites:3,totalDimensionsCites:7,abstract:"Coffee is one of the most important agricultural commodities in the world. The coffee quality is associated with pre-harvest and post-harvest management activities. Each step starting from selecting the best coffee variety for plantation until the final coffee drink preparation determines the cupping quality. The overall coffee quality influenced by the factors which involve in changes the physicochemical properties and sensorial attributes, including the post-harvest operations. The post-harvest processing activities contribute about 60% of the quality of green coffee beans. The post-harvest operations include pulping, processing, drying, hulling, cleaning, sorting, grading, storage, roasting, grinding, and cupping. This chapter comprises the harvest and post-harvest operations of coffee and their impacts on coffee quality.",book:{id:"8952",slug:"coffee-production-and-research",title:"Coffee",fullTitle:"Coffee - Production and Research"},signatures:"Mesfin Haile and Won Hee Kang",authors:null},{id:"69900",doi:"10.5772/intechopen.89508",title:"Coffee By-Products: Nowadays and Perspectives",slug:"coffee-by-products-nowadays-and-perspectives",totalDownloads:1169,totalCrossrefCites:3,totalDimensionsCites:6,abstract:"Coffee is one of the most consumed products around the world; 2.25 billions of coffee cup are consumed everyday in the world. For coffee crop production, different by-products are produced, such as coffee peel, coffee husk, parchment, and spent coffee grounds. These by-products have several problems associated at the final disposition. In this book chapter, we study the main coffee varieties produced in the world, the by-products produced, and its composition and finally assess the potential of supramolecular solvents (SUPRAS) and water as green solvents for high-added-value compound extractions. Bioactive compounds were extracted from fresh and dried coffee peel in an acceptable rate for industrial applications. SUPRAS offer advantages in terms of rapidity (5 min) and simplicity (stirring and centrifugation at room temperature), thus avoiding costly processes based on high pressure and temperature. Extractions carried out using water as solvent is another technique of extraction mixing temperature (above 60°C) and time (4.5 min) obtained a beverage or solution with presence a bioactive compounds how caffeine, chlorogenic acid and polyphenols.",book:{id:"8952",slug:"coffee-production-and-research",title:"Coffee",fullTitle:"Coffee - Production and Research"},signatures:"Laura Sofía Torres-Valenzuela, Johanna Andrea Serna-Jiménez and Katherine Martínez",authors:null}],mostDownloadedChaptersLast30Days:[{id:"71528",title:"A Detail Chemistry of Coffee and Its Analysis",slug:"a-detail-chemistry-of-coffee-and-its-analysis",totalDownloads:2410,totalCrossrefCites:5,totalDimensionsCites:6,abstract:"This review article highlights the detailed chemistry of coffee including its components; chemical constituents like carbohydrates, proteins, lipids, and caffeine; aromatic principles; oil and waxes; and minerals and acids. The high extent of caffeine can be found in the coffee plants; hence, in the second part of the study, various analytical methods are designed for the proper identification, separation, optimization, purification, and determination of caffeine present in coffee, tea, and marketed coffee. These analytical methods are appropriated for the separation and quantification of caffeine. The various analytical methods include spectroscopy methods like UV, IR, and NMR spectroscopy; chromatographic methods like paper, TLC, column, HPLC, and gas chromatography; and hyphenated techniques like LC–MS, GC–MS, and GC–MS/MS. This article compares and contrasts the amount of caffeine by various analytical methods.",book:{id:"8952",slug:"coffee-production-and-research",title:"Coffee",fullTitle:"Coffee - Production and Research"},signatures:"Hemraj Sharma",authors:null},{id:"70151",title:"The Harvest and Post-Harvest Management Practices’ Impact on Coffee Quality",slug:"the-harvest-and-post-harvest-management-practices-impact-on-coffee-quality",totalDownloads:1866,totalCrossrefCites:3,totalDimensionsCites:7,abstract:"Coffee is one of the most important agricultural commodities in the world. The coffee quality is associated with pre-harvest and post-harvest management activities. Each step starting from selecting the best coffee variety for plantation until the final coffee drink preparation determines the cupping quality. The overall coffee quality influenced by the factors which involve in changes the physicochemical properties and sensorial attributes, including the post-harvest operations. The post-harvest processing activities contribute about 60% of the quality of green coffee beans. The post-harvest operations include pulping, processing, drying, hulling, cleaning, sorting, grading, storage, roasting, grinding, and cupping. This chapter comprises the harvest and post-harvest operations of coffee and their impacts on coffee quality.",book:{id:"8952",slug:"coffee-production-and-research",title:"Coffee",fullTitle:"Coffee - Production and Research"},signatures:"Mesfin Haile and Won Hee Kang",authors:null},{id:"72400",title:"Factors Affecting Efficiency of Vegetable Production in Nigeria: A Review",slug:"factors-affecting-efficiency-of-vegetable-production-in-nigeria-a-review",totalDownloads:819,totalCrossrefCites:0,totalDimensionsCites:2,abstract:"Vegetables are important for maintenance of good health; their production and marketing are veritable sources of employment and livelihood. To promote vegetables’ contribution to the above, there is a need for sustainable and efficient production process. The paper reviewed production, socioeconomic factors, and constraint affecting efficiency of production of three important vegetables (tomato, pepper, and onion). The review showed that socioeconomic factors found to increase technical efficiency in vegetable production were educational level, extension contact, and household size. Influence of farmer age on technical efficiency was inconclusive due to varied opinions. Increase in farm size, quantity of seed, amount of fertilizer, and agrochemical were found to have positive influence on output. Majority of the literature reviewed opined that increase in quantity of labour raises productivity; however, it must be utilized efficiently. The mean technical efficiency of the vegetables varied from the southern to the northern part of the country. The cross cutting constraints in vegetables production are pest and diseases, inadequate storage facilities, and high cost of improved inputs. The study recommends increase awareness and sensitization on optimum levels of resource use for increased productivity and appropriate intervention to constraints in the value chain.",book:{id:"10142",slug:"agricultural-economics",title:"Agricultural Economics",fullTitle:"Agricultural Economics"},signatures:"Iyabo Bosede Adeoye",authors:[{id:"317695",title:"Dr.",name:"Iyabo Bosede",middleName:null,surname:"Adeoye",slug:"iyabo-bosede-adeoye",fullName:"Iyabo Bosede Adeoye"}]},{id:"65591",title:"Insect Pest Management in Organic Farming System",slug:"insect-pest-management-in-organic-farming-system",totalDownloads:2660,totalCrossrefCites:1,totalDimensionsCites:4,abstract:"Due to the regulations of organic farming, few options remain for organic farmers to manage pests and diseases in their crops compared to conventional farming. However, major pests could still be managed through manipulation of the agroecosystem processes in advantage of the crops and disadvantage of pests. The limited number of active plant protection substances authorized for use in organic farming can provide support to natural and biological control agents in suppression of pests and diseases. This chapter highlights the principles and strategies of crop protection in organic farming, the cultural practices adopted, the active substances allowed for use to suppress pests, and the impacts on faunal and floral biodiversity. A case study of organic date palm cultivation is discussed.",book:{id:"6988",slug:"multifunctionality-and-impacts-of-organic-and-conventional-agriculture",title:"Multifunctionality and Impacts of Organic and Conventional Agriculture",fullTitle:"Multifunctionality and Impacts of Organic and Conventional Agriculture"},signatures:"Hamadttu Abdel Farag El-Shafie",authors:[{id:"192142",title:"Dr.",name:"Hamadttu",middleName:null,surname:"Abdel Farag El-Shafie",slug:"hamadttu-abdel-farag-el-shafie",fullName:"Hamadttu Abdel Farag El-Shafie"}]},{id:"69412",title:"Soil Management and Water-Use Efficiency in Brazilian Coffee Crops",slug:"soil-management-and-water-use-efficiency-in-brazilian-coffee-crops",totalDownloads:817,totalCrossrefCites:1,totalDimensionsCites:1,abstract:"Brazil is a world leader in coffee production. However, currently, it coexists with recurrent and severe droughts, accompanied by intense heat, strong insolation and low relative humidity. As the cultivation is carried out primarily in the rainy season, these world climate variations have affected crops yields and fruits quality, requiring innovative actions that promote efficient use of water stored in the soil. Among several soil management practices that promote a more rational use of water, deep tillage combined with liming, gypsum and fertilizer amendments lead to an increase in effective depth of coffee roots, therefore reducing water stress. Moreover, intercropping with Urochloa sp. is highly efficient in enhancing soil structure, water infiltration and plant available water capacity. Additionally, other innovative techniques and practices are also introduced in this chapter.",book:{id:"8952",slug:"coffee-production-and-research",title:"Coffee",fullTitle:"Coffee - Production and Research"},signatures:"Bruno Montoani Silva, Geraldo César de Oliveira, Milson Evaldo Serafim, Carla Eloize Carducci, Érika Andressa da Silva, Samara Martins Barbosa, Laura Beatriz Batista de Melo, Walbert Junior Reis dos Santos, Thiago Henrique Pereira Reis, César Henrique Caputo de Oliveira and Paulo Tácito Gontijo Guimarães",authors:null}],onlineFirstChaptersFilter:{topicId:"27",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:8,limit:8,total:0},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:90,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:108,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:33,numberOfPublishedChapters:330,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:14,numberOfPublishedChapters:145,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:9,numberOfPublishedChapters:140,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:123,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:112,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:22,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:11,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:"2753-6580",doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. The whole process of submitting an article and editing of the submitted article goes extremely smooth and fast, the number of reads and downloads of chapters is high, and the contributions are also frequently cited.",author:{id:"55578",name:"Antonio",surname:"Jurado-Navas",institutionString:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",slug:"antonio-jurado-navas",institution:{id:"720",name:"University of Malaga",country:{id:null,name:"Spain"}}}},{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}}]},series:{item:{id:"11",title:"Biochemistry",doi:"10.5772/intechopen.72877",issn:"2632-0983",scope:"Biochemistry, the study of chemical transformations occurring within living organisms, impacts all areas of life sciences, from molecular crystallography and genetics to ecology, medicine, and population biology. Biochemistry examines macromolecules - proteins, nucleic acids, carbohydrates, and lipids – and their building blocks, structures, functions, and interactions. Much of biochemistry is devoted to enzymes, proteins that catalyze chemical reactions, enzyme structures, mechanisms of action and their roles within cells. Biochemistry also studies small signaling molecules, coenzymes, inhibitors, vitamins, and hormones, which play roles in life processes. Biochemical experimentation, besides coopting classical chemistry methods, e.g., chromatography, adopted new techniques, e.g., X-ray diffraction, electron microscopy, NMR, radioisotopes, and developed sophisticated microbial genetic tools, e.g., auxotroph mutants and their revertants, fermentation, etc. More recently, biochemistry embraced the ‘big data’ omics systems. Initial biochemical studies have been exclusively analytic: dissecting, purifying, and examining individual components of a biological system; in the apt words of Efraim Racker (1913 –1991), “Don’t waste clean thinking on dirty enzymes.” Today, however, biochemistry is becoming more agglomerative and comprehensive, setting out to integrate and describe entirely particular biological systems. The ‘big data’ metabolomics can define the complement of small molecules, e.g., in a soil or biofilm sample; proteomics can distinguish all the comprising proteins, e.g., serum; metagenomics can identify all the genes in a complex environment, e.g., the bovine rumen. This Biochemistry Series will address the current research on biomolecules and the emerging trends with great promise.",coverUrl:"https://cdn.intechopen.com/series/covers/11.jpg",latestPublicationDate:"August 2nd, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:33,editor:{id:"31610",title:"Dr.",name:"Miroslav",middleName:null,surname:"Blumenberg",slug:"miroslav-blumenberg",fullName:"Miroslav Blumenberg",profilePictureURL:"https://mts.intechopen.com/storage/users/31610/images/system/31610.jpg",biography:"Miroslav Blumenberg, Ph.D., was born in Subotica and received his BSc in Belgrade, Yugoslavia. He completed his Ph.D. at MIT in Organic Chemistry; he followed up his Ph.D. with two postdoctoral study periods at Stanford University. Since 1983, he has been a faculty member of the RO Perelman Department of Dermatology, NYU School of Medicine, where he is codirector of a training grant in cutaneous biology. Dr. Blumenberg’s research is focused on the epidermis, expression of keratin genes, transcription profiling, keratinocyte differentiation, inflammatory diseases and cancers, and most recently the effects of the microbiome on the skin. He has published more than 100 peer-reviewed research articles and graduated numerous Ph.D. and postdoctoral students.",institutionString:null,institution:{name:"New York University Langone Medical Center",institutionURL:null,country:{name:"United States of America"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:4,paginationItems:[{id:"14",title:"Cell and Molecular Biology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/14.jpg",isOpenForSubmission:!0,editor:{id:"165627",title:"Dr.",name:"Rosa María",middleName:null,surname:"Martínez-Espinosa",slug:"rosa-maria-martinez-espinosa",fullName:"Rosa María Martínez-Espinosa",profilePictureURL:"https://mts.intechopen.com/storage/users/165627/images/system/165627.jpeg",biography:"Dr. Rosa María Martínez-Espinosa has been a Spanish Full Professor since 2020 (Biochemistry and Molecular Biology) and is currently Vice-President of International Relations and Cooperation development and leader of the research group 'Applied Biochemistry” (University of Alicante, Spain). Other positions she has held at the university include Vice-Dean of Master Programs, Vice-Dean of the Degree in Biology and Vice-Dean for Mobility and Enterprise and Engagement at the Faculty of Science (University of Alicante). She received her Bachelor in Biology in 1998 (University of Alicante) and her PhD in 2003 (Biochemistry, University of Alicante). She undertook post-doctoral research at the University of East Anglia (Norwich, U.K. 2004-2005; 2007-2008).\nHer multidisciplinary research focuses on investigating archaea and their potential applications in biotechnology. She has an H-index of 21. She has authored one patent and has published more than 70 indexed papers and around 60 book chapters.\nShe has contributed to more than 150 national and international meetings during the last 15 years. Her research interests include archaea metabolism, enzymes purification and characterization, gene regulation, carotenoids and bioplastics production, antioxidant\ncompounds, waste water treatments, and brines bioremediation.\nRosa María’s other roles include editorial board member for several journals related\nto biochemistry, reviewer for more than 60 journals (biochemistry, molecular biology, biotechnology, chemistry and microbiology) and president of several organizing committees in international meetings related to the N-cycle or respiratory processes.",institutionString:null,institution:{name:"University of Alicante",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null},{id:"15",title:"Chemical Biology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/15.jpg",isOpenForSubmission:!0,editor:{id:"441442",title:"Dr.",name:"Şükrü",middleName:null,surname:"Beydemir",slug:"sukru-beydemir",fullName:"Şükrü Beydemir",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003GsUoIQAV/Profile_Picture_1634557147521",biography:"Dr. Şükrü Beydemir obtained a BSc in Chemistry in 1995 from Yüzüncü Yıl University, MSc in Biochemistry in 1998, and PhD in Biochemistry in 2002 from Atatürk University, Turkey. He performed post-doctoral studies at Max-Planck Institute, Germany, and University of Florence, Italy in addition to making several scientific visits abroad. He currently works as a Full Professor of Biochemistry in the Faculty of Pharmacy, Anadolu University, Turkey. Dr. Beydemir has published over a hundred scientific papers spanning protein biochemistry, enzymology and medicinal chemistry, reviews, book chapters and presented several conferences to scientists worldwide. He has received numerous publication awards from various international scientific councils. He serves in the Editorial Board of several international journals. Dr. Beydemir is also Rector of Bilecik Şeyh Edebali University, Turkey.",institutionString:null,institution:{name:"Anadolu University",institutionURL:null,country:{name:"Turkey"}}},editorTwo:{id:"13652",title:"Prof.",name:"Deniz",middleName:null,surname:"Ekinci",slug:"deniz-ekinci",fullName:"Deniz Ekinci",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYLT1QAO/Profile_Picture_1634557223079",biography:"Dr. Deniz Ekinci obtained a BSc in Chemistry in 2004, MSc in Biochemistry in 2006, and PhD in Biochemistry in 2009 from Atatürk University, Turkey. He studied at Stetson University, USA, in 2007-2008 and at the Max Planck Institute of Molecular Cell Biology and Genetics, Germany, in 2009-2010. Dr. Ekinci currently works as a Full Professor of Biochemistry in the Faculty of Agriculture and is the Head of the Enzyme and Microbial Biotechnology Division, Ondokuz Mayıs University, Turkey. He is a member of the Turkish Biochemical Society, American Chemical Society, and German Genetics society. Dr. Ekinci published around ninety scientific papers, reviews and book chapters, and presented several conferences to scientists. He has received numerous publication awards from several scientific councils. Dr. Ekinci serves as the Editor in Chief of four international books and is involved in the Editorial Board of several international journals.",institutionString:null,institution:{name:"Ondokuz Mayıs University",institutionURL:null,country:{name:"Turkey"}}},editorThree:null},{id:"17",title:"Metabolism",coverUrl:"https://cdn.intechopen.com/series_topics/covers/17.jpg",isOpenForSubmission:!0,editor:{id:"138626",title:"Dr.",name:"Yannis",middleName:null,surname:"Karamanos",slug:"yannis-karamanos",fullName:"Yannis Karamanos",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002g6Jv2QAE/Profile_Picture_1629356660984",biography:"Yannis Karamanos, born in Greece in 1953, completed his pre-graduate studies at the Université Pierre et Marie Curie, Paris, then his Masters and Doctoral degree at the Université de Lille (1983). He was associate professor at the University of Limoges (1987) before becoming full professor of biochemistry at the Université d’Artois (1996). He worked on the structure-function relationships of glycoconjugates and his main project was the investigations on the biological roles of the de-N-glycosylation enzymes (Endo-N-acetyl-β-D-glucosaminidase and peptide-N4-(N-acetyl-β-glucosaminyl) asparagine amidase). From 2002 he contributes to the understanding of the Blood-brain barrier functioning using proteomics approaches. He has published more than 70 papers. His teaching areas are energy metabolism and regulation, integration and organ specialization and metabolic adaptation.",institutionString:null,institution:{name:"Artois University",institutionURL:null,country:{name:"France"}}},editorTwo:null,editorThree:null},{id:"18",title:"Proteomics",coverUrl:"https://cdn.intechopen.com/series_topics/covers/18.jpg",isOpenForSubmission:!0,editor:{id:"200689",title:"Prof.",name:"Paolo",middleName:null,surname:"Iadarola",slug:"paolo-iadarola",fullName:"Paolo Iadarola",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSCl8QAG/Profile_Picture_1623568118342",biography:"Paolo Iadarola graduated with a degree in Chemistry from the University of Pavia (Italy) in July 1972. He then worked as an Assistant Professor at the Faculty of Science of the same University until 1984. In 1985, Prof. Iadarola became Associate Professor at the Department of Biology and Biotechnologies of the University of Pavia and retired in October 2017. Since then, he has been working as an Adjunct Professor in the same Department at the University of Pavia. His research activity during the first years was primarily focused on the purification and structural characterization of enzymes from animal and plant sources. During this period, Prof. Iadarola familiarized himself with the conventional techniques used in column chromatography, spectrophotometry, manual Edman degradation, and electrophoresis). Since 1995, he has been working on: i) the determination in biological fluids (serum, urine, bronchoalveolar lavage, sputum) of proteolytic activities involved in the degradation processes of connective tissue matrix, and ii) on the identification of biological markers of lung diseases. In this context, he has developed and validated new methodologies (e.g., Capillary Electrophoresis coupled to Laser-Induced Fluorescence, CE-LIF) whose application enabled him to determine both the amounts of biochemical markers (Desmosines) in urine/serum of patients affected by Chronic Obstructive Pulmonary Disease (COPD) and the activity of proteolytic enzymes (Human Neutrophil Elastase, Cathepsin G, Pseudomonas aeruginosa elastase) in sputa of these patients. More recently, Prof. Iadarola was involved in developing techniques such as two-dimensional electrophoresis coupled to liquid chromatography/mass spectrometry (2DE-LC/MS) for the proteomic analysis of biological fluids aimed at the identification of potential biomarkers of different lung diseases. He is the author of about 150 publications (According to Scopus: H-Index: 23; Total citations: 1568- According to WOS: H-Index: 20; Total Citations: 1296) of peer-reviewed international journals. He is a Consultant Reviewer for several journals, including the Journal of Chromatography A, Journal of Chromatography B, Plos ONE, Proteomes, International Journal of Molecular Science, Biotech, Electrophoresis, and others. He is also Associate Editor of Biotech.",institutionString:null,institution:{name:"University of Pavia",institutionURL:null,country:{name:"Italy"}}},editorTwo:{id:"201414",title:"Dr.",name:"Simona",middleName:null,surname:"Viglio",slug:"simona-viglio",fullName:"Simona Viglio",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRKDHQA4/Profile_Picture_1630402531487",biography:"Simona Viglio is an Associate Professor of Biochemistry at the Department of Molecular Medicine at the University of Pavia. She has been working since 1995 on the determination of proteolytic enzymes involved in the degradation process of connective tissue matrix and on the identification of biological markers of lung diseases. 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Finally, the tissue engineering subcategory will support topics such as the fundamentals of stem cells and progenitor cells and their proliferation, differentiation, bioreactors for three-dimensional culture and studies of phenotypic changes, stem and progenitor cells, both short and long term, ex vivo and in vivo implantation both in preclinical models and also in clinical trials.",annualVolume:11405,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/9.jpg",editor:{id:"126286",title:"Dr.",name:"Luis",middleName:"Jesús",surname:"Villarreal-Gómez",fullName:"Luis Villarreal-Gómez",profilePictureURL:"https://mts.intechopen.com/storage/users/126286/images/system/126286.jpg",institutionString:null,institution:{name:"Autonomous University of Baja California",institutionURL:null,country:{name:"Mexico"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"35539",title:"Dr.",name:"Cecilia",middleName:null,surname:"Cristea",fullName:"Cecilia Cristea",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYQ65QAG/Profile_Picture_1621007741527",institutionString:null,institution:{name:"Iuliu Hațieganu University of Medicine and Pharmacy",institutionURL:null,country:{name:"Romania"}}},{id:"40735",title:"Dr.",name:"Gil",middleName:"Alberto Batista",surname:"Gonçalves",fullName:"Gil Gonçalves",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYRLGQA4/Profile_Picture_1628492612759",institutionString:null,institution:{name:"University of Aveiro",institutionURL:null,country:{name:"Portugal"}}},{id:"211725",title:"Associate Prof.",name:"Johann F.",middleName:null,surname:"Osma",fullName:"Johann F. 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