Indices of hypoperfusion and their targets.
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Barely three months into the new year and we are happy to announce a monumental milestone reached - 150 million downloads.
\n\nThis achievement solidifies IntechOpen’s place as a pioneer in Open Access publishing and the home to some of the most relevant scientific research available through Open Access.
\n\nWe are so proud to have worked with so many bright minds throughout the years who have helped us spread knowledge through the power of Open Access and we look forward to continuing to support some of the greatest thinkers of our day.
\n\nThank you for making IntechOpen your place of learning, sharing, and discovery, and here’s to 150 million more!
\n\n\n\n\n'}],latestNews:[{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"},{slug:"introducing-intechopen-book-series-a-new-publishing-format-for-oa-books-20210915",title:"Introducing IntechOpen Book Series - A New Publishing Format for OA Books"}]},book:{item:{type:"book",id:"10348",leadTitle:null,fullTitle:"Addictions - Diagnosis and Treatment",title:"Addictions",subtitle:"Diagnosis and Treatment",reviewType:"peer-reviewed",abstract:"This book addresses the diagnosis and treatment of drug addiction. Chapters in this book span biological, psychological, cultural, and health-based perspectives and emphasize meeting people as they really are in order to obtain tangible advances in clinical practice. These works represent the integration of the past, present, and likely future directions of both diagnosis and treatment. Addiction is an individual and systemic challenge to society and scientific advances and cultural diversity are highlighted here as paths forward towards addressing current diagnostic and treatment obstacles.",isbn:"978-1-83968-633-7",printIsbn:"978-1-83968-632-0",pdfIsbn:"978-1-83968-634-4",doi:"10.5772/intechopen.91534",price:119,priceEur:129,priceUsd:155,slug:"addictions-diagnosis-and-treatment",numberOfPages:270,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"4b66187e9866019abbb18183e4364d2b",bookSignature:"William M. Meil and John A. Mills",publishedDate:"October 13th 2021",coverURL:"https://cdn.intechopen.com/books/images_new/10348.jpg",numberOfDownloads:2154,numberOfWosCitations:2,numberOfCrossrefCitations:3,numberOfCrossrefCitationsByBook:0,numberOfDimensionsCitations:5,numberOfDimensionsCitationsByBook:0,hasAltmetrics:1,numberOfTotalCitations:10,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"August 31st 2020",dateEndSecondStepPublish:"November 4th 2020",dateEndThirdStepPublish:"January 3rd 2021",dateEndFourthStepPublish:"March 24th 2021",dateEndFifthStepPublish:"May 23rd 2021",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"87876",title:"Dr.",name:"William M.",middleName:null,surname:"Meil",slug:"william-m.-meil",fullName:"William M. Meil",profilePictureURL:"https://mts.intechopen.com/storage/users/87876/images/system/87876.jpg",biography:"Dr. William M. Meil is a full professor in the Psychology Department, Indiana University of Pennsylvania. Previously, he was a postdoctoral fellow at The Northeastern Ohio Universities Colleges of Medicine and Pharmacy. He received an MA in Psychology from The University of Hartford, Connecticut, and a Ph.D. in Psychology from Washington State University, Pullman, Washington. His research has spanned human and laboratory animal studies investigating the neurobiological basis of substance abuse and addiction. The current focus of his research is the examination of executive function, emotion regulation, and impulsivity as predictors of addictive behavior and recovery from addiction. He is the author of many peer-reviewed journal articles and book chapters.",institutionString:"Indiana University of Pennsylvania",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"2",totalChapterViews:"0",totalEditedBooks:"2",institution:{name:"Indiana University of Pennsylvania",institutionURL:null,country:{name:"United States of America"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:{id:"180728",title:"Dr.",name:"John A.",middleName:null,surname:"Mills",slug:"john-a.-mills",fullName:"John A. Mills",profilePictureURL:"https://mts.intechopen.com/storage/users/180728/images/system/180728.png",biography:"Dr. John Mills completed a BA with distinction in Psychology, an MEd in Counseling, and a Ph.D. in Counseling Psychology. He has since completed an MS in Sports Science and graduated education in music (low brass). He has worked for more than three decades as a clinician and clinician educator in both mental health and substance abuse therapeutics. He currently teaches psychology at the undergraduate and doctoral levels, and he has published and presented in a number of areas that have emphasized ethics, clinical practice, and clinical supervision. He is board-certified in counseling psychology by the American Board of Professional Psychology and is a registrant with the National Register of Health Service Psychologists.",institutionString:"Indiana University of Pennsylvania",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"2",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Indiana University of Pennsylvania",institutionURL:null,country:{name:"United States of America"}}},coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"1061",title:"Psychiatry",slug:"mental-and-behavioural-disorders-and-diseases-of-the-nervous-system-psychiatry"}],chapters:[{id:"78225",title:"Psychopharmacological Perspectives and Diagnosis of Substance Use Disorder",doi:"10.5772/intechopen.99531",slug:"psychopharmacological-perspectives-and-diagnosis-of-substance-use-disorder",totalDownloads:223,totalCrossrefCites:0,totalDimensionsCites:1,hasAltmetrics:0,abstract:"A considerable body of research has accumulated over several decades and altered the current understanding of substance use and its effects on the brain. This knowledge has improved the perception of the disease of addiction and has opened the door to new ways of thinking about diagnosis, prevention, and treatment of substance use disorders. The purpose of the current chapter is to briefly outline and summarize the major psychopharmacological framework underlying substance use disorder (SUD) and the factors that involve in the transformation of some people from recreational use or misuse of alcohol or drugs to SUD. The chapter explains the overall neurocircuitry theories of the addiction cycle: binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation. It briefly discusses how psychoactive substances produce changes in brain functioning that facilitate the development of addiction and contribute to craving which eventually leads to relapse. The chapter also deals with similarities and differences among various classes of addictive substances in their effects on the brain and behavior and briefly describes the main risk factors that involve SUD. Finally, an attempt is made to briefly discuss the major DSM 5 based behavioral criteria that involve SUD, corresponding to the most abused substances worldwide.",signatures:"Samson Duresso",downloadPdfUrl:"/chapter/pdf-download/78225",previewPdfUrl:"/chapter/pdf-preview/78225",authors:[{id:"337196",title:"Dr.",name:"Samson",surname:"Duresso",slug:"samson-duresso",fullName:"Samson Duresso"}],corrections:null},{id:"74834",title:"The Juramento: Secondary and Tertiary Preventive Benefits of a Religious-Based Brief Alcohol Intervention in the Mexican Immigrant Community",doi:"10.5772/intechopen.95545",slug:"the-em-juramento-em-secondary-and-tertiary-preventive-benefits-of-a-religious-based-brief-alcohol-in",totalDownloads:138,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Our chapter addresses the prevention benefits of the juramento, a grassroots religious-based brief intervention for harmful drinking practiced in Mexico and the Mexican immigrant community in the United States. With origins in Mexican folk Catholicism, it is a sacred pledge made to Our Lady of Guadalupe to abstain from alcohol for a specific time period; in most cases, at least six months. We draw on our data from a subsample of 15 Mexican workers who made juramentos and two priests who administered the juramento to the workers. The sample is from a larger qualitative study on the use of the juramento among Mexican immigrant and migrant workers in southeastern Pennsylvania. Our findings reveal that, in addition to serving as an intervention, the juramento results in secondary prevention—by identifying a harmful drinking before the onset of heavy drinking—and tertiary prevention—by slowing or abating the progression of heavy drinking.",signatures:"Victor Garcia, Katherine Fox, Emily Lambert and Alex Heckert",downloadPdfUrl:"/chapter/pdf-download/74834",previewPdfUrl:"/chapter/pdf-preview/74834",authors:[{id:"331727",title:"Distinguished Prof.",name:"Victor",surname:"Garcia",slug:"victor-garcia",fullName:"Victor Garcia"},{id:"331927",title:"Prof.",name:"Alex",surname:"Heckert",slug:"alex-heckert",fullName:"Alex Heckert"},{id:"331928",title:"Ms.",name:"Emily",surname:"Lambert",slug:"emily-lambert",fullName:"Emily Lambert"},{id:"344968",title:"Dr.",name:"Katherine",surname:"Fox",slug:"katherine-fox",fullName:"Katherine Fox"}],corrections:null},{id:"75689",title:"Sex Differences between Young Adults in the Czech and Slovak Republics in the Relationship between Alcohol-Related Consequences and Depression",doi:"10.5772/intechopen.96469",slug:"sex-differences-between-young-adults-in-the-czech-and-slovak-republics-in-the-relationship-between-a",totalDownloads:188,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:0,abstract:"In general, the Czech and Slovak Republic are among the countries with increased alcohol consumption. It is clear that increased consumption can predict the occurrence of negative consequences that may subsequently be associated with various mental disorders. One of these mental disorders is depression, which is common in young adults and brings difficulties into their lives that can turn into problems in the future. The study examined the relationship between alcohol-related consequences and depressive symptoms in a sample of university students from the Czech and Slovak Republics in order to map the situation in these regions, where this problem is still ignored (n = 2514; CZE = 47.5%). The research included data from standardized questionnaires, namely the Young Adult Alcohol Consequences Questionnaire (YAACQ), which can predict alcohol use problems, and Health Questionnaire of depression (PHQ-9). The data was collected during the COVID-19 pandemic. Regarding sex differences, a higher YAACQ score was found in males and, conversely, a higher PHQ-9 score was identified in females. The results of correlation and regression analyses revealed significant associations between the scores in the individual YAACQ subscales and the PHQ-9 score, while low to moderate correlations were found in most cases. In all cases, positive trajectories were identified, meaning that the increased risk of depressive disorder can be associated with experience in selected dimensions of alcohol-related consequences. Stronger associations occurred in females than in males. In terms of practical implications, high priority was given to prevention programs and counseling. Professionals’ efforts to help young people should be sex-oriented, while females were more vulnerable to depression, males were prone to the consequences of alcohol use.",signatures:"Beata Gavurova, Martin Rigelsky and Viera Ivankova",downloadPdfUrl:"/chapter/pdf-download/75689",previewPdfUrl:"/chapter/pdf-preview/75689",authors:[{id:"197261",title:"Prof.",name:"Beata",surname:"Gavurova",slug:"beata-gavurova",fullName:"Beata Gavurova"},{id:"336547",title:"Mr.",name:"Martin",surname:"Rigelsky",slug:"martin-rigelsky",fullName:"Martin Rigelsky"},{id:"336548",title:"Mrs.",name:"Viera",surname:"Ivankova",slug:"viera-ivankova",fullName:"Viera Ivankova"}],corrections:null},{id:"78693",title:"Leveraging Advanced Analytics to Understand the Impact of the COVID-19 Pandemic on Trends in Substance Use Disorders",doi:"10.5772/intechopen.99639",slug:"leveraging-advanced-analytics-to-understand-the-impact-of-the-covid-19-pandemic-on-trends-in-substan",totalDownloads:147,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:1,abstract:"Coronavirus disease (COVID-19) caused an overwhelming healthcare, economic, social, and psychological impact on the world during 2020 and first part of 2021. Certain populations, especially those with Substance Use Disorders (SUD), were particularly vulnerable to contract the virus and also likely to suffer from a greater psychosocial and psychological burden. COVID-19 and addiction are two conditions on the verge of a collision, potentially causing a major public health threat. There is surge of addictive behaviors (both new and relapse), including use of alcohol, nicotine, and recreational drugs. This book chapter analyzed the bi-directional relationship between COVID-19 and SUD by leveraging descriptive summaries, advanced analytics, and machine learning approaches. The data sources included healthcare claims dataset as well as state level alcohol consumption to help in investigating the bi-directional relationship between the two conditions. Results suggest that alcohol and nicotine use increased during the pandemic and that the profile of SUD patients included diagnoses and symptoms of COVID-19, depression and anxiety, as well as hypertensive conditions.",signatures:"Ewa J. Kleczyk, Jill Bana and Rishabh Arora",downloadPdfUrl:"/chapter/pdf-download/78693",previewPdfUrl:"/chapter/pdf-preview/78693",authors:[{id:"346273",title:"Dr.",name:"Ewa J.",surname:"Kleczyk",slug:"ewa-j.-kleczyk",fullName:"Ewa J. Kleczyk"},{id:"346346",title:"Ms.",name:"Jill",surname:"Bana",slug:"jill-bana",fullName:"Jill Bana"},{id:"423766",title:"Mr.",name:"Rishabh",surname:"Arora",slug:"rishabh-arora",fullName:"Rishabh Arora"}],corrections:null},{id:"75130",title:"Revisiting 12-Step Approaches: An Evidence-Based Perspective",doi:"10.5772/intechopen.95985",slug:"revisiting-12-step-approaches-an-evidence-based-perspective",totalDownloads:531,totalCrossrefCites:1,totalDimensionsCites:2,hasAltmetrics:1,abstract:"Alcoholics Anonymous (AA) is the longest-running mutual aid group for people with alcohol use disorders, and AA turned 85 years old in 2020. Though there has been much criticism regarding AA and other 12-step programs, there has been an equal amount of evidence to support their efficacy. This chapter explores the history of AA and other 12-step approaches, the foundational philosophy of the 12-steps, the key elements that support recovery, cultural considerations for special populations, and a review of the criticisms as well as strengths of 12-step approaches. The chapter concludes with recommendations for the integration of the approach into clinical practice.",signatures:"Dorothy Greene",downloadPdfUrl:"/chapter/pdf-download/75130",previewPdfUrl:"/chapter/pdf-preview/75130",authors:[{id:"330237",title:"Associate Prof.",name:"Dorothy",surname:"Greene",slug:"dorothy-greene",fullName:"Dorothy Greene"}],corrections:null},{id:"76404",title:"Assessment and Treatment of Addictions in Community Corrections",doi:"10.5772/intechopen.96770",slug:"assessment-and-treatment-of-addictions-in-community-corrections",totalDownloads:313,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:1,abstract:"This chapter discusses the treatment of substance use disorders within community corrections populations. The history of substance abuse treatment within correctional populations is outlined to provide context for the current diversion and rehabilitation models currently in use. Common systems where treatment is provided such as mental health court, drug court, and TASC are described. Common forms of therapy including Cognitive Behavioral Therapy, Mindfulness, social skills training, pharmacotherapy, and smoking cessation are discussed. This chapter focuses on their effectiveness as well as how these forms of therapy differ in community corrections as compared to other populations. Finally, recommendations and future directions for research are provided.",signatures:"Jacob D. Armstrong, Amy Bauman, Krystal J. Moroney and C. Brendan Clark",downloadPdfUrl:"/chapter/pdf-download/76404",previewPdfUrl:"/chapter/pdf-preview/76404",authors:[{id:"338509",title:"Associate Prof.",name:"Brendan",surname:"Clark",slug:"brendan-clark",fullName:"Brendan Clark"},{id:"345513",title:"Mr.",name:"Jacob D.",surname:"Armstrong",slug:"jacob-d.-armstrong",fullName:"Jacob D. Armstrong"},{id:"345514",title:"Ms.",name:"Amy",surname:"Bauman",slug:"amy-bauman",fullName:"Amy Bauman"},{id:"345515",title:"Ms.",name:"Krystal J.",surname:"Moroney",slug:"krystal-j.-moroney",fullName:"Krystal J. Moroney"}],corrections:null},{id:"74882",title:"Conceptualizing Drug Addiction and Chronic Pain through a Biopsychosocial Framework to Improve Therapeutic Strategies",doi:"10.5772/intechopen.95601",slug:"conceptualizing-drug-addiction-and-chronic-pain-through-a-biopsychosocial-framework-to-improve-thera",totalDownloads:152,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"The recent surge in opioid-related deaths has brought poor pain management practices to the forefront of our nation’s collective consciousness. However, improving treatments for chronic pain, substance use disorders (SUD), and comorbid expression of both requires a better understanding of the pathophysiology involved in their development. In this chapter, the authors present the argument that chronic pain and SUD can be conceptualized similarly from a biopsychosocial perspective to inform a better approach to treatment. The authors describe the common neurobehavioral mechanisms of SUD and chronic pain, then discuss the efficacy of several psychotherapeutic methods employed to combat chronic pain, addiction, and related disorders. Such methods may contribute to positive health outcomes in managing chronic pain and curbing drug addiction by reducing the role of opioid analgesics for long-term pain management.",signatures:"Zachary S. Harmon, Emily N. Welch and Christina L. Ruby",downloadPdfUrl:"/chapter/pdf-download/74882",previewPdfUrl:"/chapter/pdf-preview/74882",authors:[{id:"331511",title:"Associate Prof.",name:"Christina L.",surname:"Ruby",slug:"christina-l.-ruby",fullName:"Christina L. Ruby"},{id:"331513",title:"Mr.",name:"Zachary S.",surname:"Harmon",slug:"zachary-s.-harmon",fullName:"Zachary S. Harmon"},{id:"331515",title:"MSc.",name:"Emily N.",surname:"Welch",slug:"emily-n.-welch",fullName:"Emily N. Welch"}],corrections:null},{id:"76483",title:"Supervision of Substance Abuse Therapeutics Emphasizing the Discrimination Model of Supervision and Motivational Interview Practices",doi:"10.5772/intechopen.97626",slug:"supervision-of-substance-abuse-therapeutics-emphasizing-the-discrimination-model-of-supervision-and-",totalDownloads:222,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"There is considerable pressure from varied sources to provide effective supervision to professionals who deliver therapeutic services to persons being treated for substance use disorders. The literature of supervision continues to evolve as the utility of supervision models and their applicability with substance abuse therapeutics are explored. Among the many models of supervision, Bernard’s Discrimination Model of supervision is experiencing on-going development in the context of a variety of clinical services. The current chapter will describe how Bernard’s model can be used effectively to enhance the supervision of substance abuse professionals as well as how further development of the model would enhance the approach. The Discrimination Model will be combined with existing literature of Motivational Interviewing approaches to describe key elements of effective clinical supervision with professionals delivering services in a complex and challenging industry.",signatures:"John A. Mills and Maren Krizner",downloadPdfUrl:"/chapter/pdf-download/76483",previewPdfUrl:"/chapter/pdf-preview/76483",authors:[{id:"180728",title:"Dr.",name:"John A.",surname:"Mills",slug:"john-a.-mills",fullName:"John A. Mills"},{id:"347551",title:"Dr.",name:"Maren",surname:"Krizner",slug:"maren-krizner",fullName:"Maren Krizner"}],corrections:null},{id:"77210",title:"An Evaluation of Diverse Therapeutic Interventions for Substance Use Disorders: Serotonergic Hallucinogens, Immunotherapy, and Transcranial Magnetic Stimulation",doi:"10.5772/intechopen.98514",slug:"an-evaluation-of-diverse-therapeutic-interventions-for-substance-use-disorders-serotonergic-hallucin",totalDownloads:240,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Substance Use Disorders are a substantial public health concern whose treatment remains challenging. High rates of relapse are in fact a hallmark of drug addiction despite the wide variety of psychotherapeutic and pharmacotherapeutic approaches. This chapter discusses three innovative and controversial therapeutic approaches for Substance Use Disorders that have received considerable attention: the use of classic serotonergic hallucinogenic drugs (LSD and psilocybin), addiction immunotherapy and anti-addiction vaccines, and the use of transcranial magnetic stimulation. These treatments are not necessarily new but are discussed because they represent a diverse set of approaches that address varied aspects of drug addiction. Furthermore, they have an accumulated body of research from which to assess their future viability. For each of these therapeutic approaches this chapter considers the theoretical basis for use, history, status of the literature supporting their use, limitations, and potential applications. While these three interventions represent highly varied approaches to the treatment of Substance Use Disorders, this diversity may be necessary given the complex nature of addictive disorders.",signatures:"William M. Meil, William Farrell and Reem Satti",downloadPdfUrl:"/chapter/pdf-download/77210",previewPdfUrl:"/chapter/pdf-preview/77210",authors:[{id:"87876",title:"Dr.",name:"William M.",surname:"Meil",slug:"william-m.-meil",fullName:"William M. Meil"},{id:"333465",title:"Dr.",name:"William J.",surname:"Farrell",slug:"william-j.-farrell",fullName:"William J. Farrell"},{id:"344967",title:"Ms.",name:"Reem",surname:"Satti",slug:"reem-satti",fullName:"Reem Satti"}],corrections:null}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},subseries:null,tags:null},relatedBooks:[{type:"book",id:"5171",title:"Recent Advances in Drug Addiction Research and Clinical Applications",subtitle:null,isOpenForSubmission:!1,hash:"d4d43741fe591f3102735d26db3c51a0",slug:"recent-advances-in-drug-addiction-research-and-clinical-applications",bookSignature:"William M. Meil and Christina L. 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Vitamin E, an important nutrient in the human diet that is readily available in lipid-rich plant products, is well known for its antioxidant properties with multiple health benefits. Historically, drug discovery researches have focused on natural products that abound in biological compounds with pharmacologic properties [1]. The discovery of vitamin E began in 1922 when Herbert Evans and Katherine Bishop [2] isolated an uncharacterised fat-soluble compound (which they termed ‘substance X’) from green leafy vegetables that they imagined might play a role in fertility. When the compound was finally identified in 1924, it was named tocopherol — derived from the Greek word tokos meaning childbirth and pheros which means to bring forth [3]. Vitamin E was rediscovered as ‘factor 2 antioxidant’ in 1965 [4]. Not surprisingly, as the major isoform of Vitamin E ever identified, α-tocopherol was thrust into the limelight while its sisters were ignored. Tocopherol is regarded as the most biologically active and potent antioxidant currently in existence. However, recent studies have shown that tocotrienols may have superior anti-oxidant [5], anti-inflammatory [6], anti-cholesterolaemic, [7, 8, 9, 10, 11] anti-cancer [12, 13], anti-diabetic [14, 15, 16], anti-atherogenic [17, 18], blood pressure lowering, [19, 20] and neuroprotective effects [21, 22, 23]. Unfortunately, despite the recent interest in tocotrienols, it comprises only 3% of all vitamin E research papers listed in PubMed [24].
Generally, vitamin E is classified into tocopherols and tocotrienols, and there are eight isoforms altogether: α-, β-, γ-, and δ-tocopherol, and α-, β-, γ-, and δ-tocotrienol. Structurally, they are very similar and possess a chromanol head formed by phenolic and heterocyclic rings, and a phenyl tail [25]. Designation as α-, β-, γ- or δ-tocopherol or tocotrienols is dependent on the methyl substitutions on the phenolic ring [26]. The main difference between the two groups is that tocopherols have a long-saturated carbon side-chain with chiral centres, whereas tocotrienols possess three unsaturated bonds in the carbon side-chain with one chiral centre [27]. This unique property somehow increases the efficiency of tocotrienols in its metabolic function; it allows a better penetration of saturated fatty layers by tocotrienols as compared to tocopherols. Figure 1 above illustrates the difference between the structures of tocopherols and tocotrienols [28].
The different structures between tocopherols and tocotrienols.
Vitamin E occurs naturally in vegetables, plants and plant oils. With regard to tocopherols, α-tocopherol is generally found in green leafy plants while γ-tocopherol occurs in the non-green parts of the plants, notably seeds and fruits [29]. Based on the United States Department of Agriculture nutrient database, α-tocopherol is commonly found in almonds, avocados, hazelnuts, peanuts and sunflower seeds; β-tocopherol in oregano and poppy seeds; γ-tocopherol in pecans, pistachios, sesame seeds and walnuts; and δ-tocopherol in edamame and raspberries. Both α-tocopherol and γ-tocopherol are present in food oils such as corn, peanut and soybean oil. Conversely, tocotrienols are rarely found in food sources or vegetable oils, with rice bran and palm oil being the only known exceptions. This explains the scarcity of scientific literature on tocotrienols compared to tocopherols as a form of vitamin E that is widely accepted by the public. In fact, most people are unaware that up to 70% of vitamin E from crude palm oil consists of tocotrienols [30, 31]. Studies have proven that the extraction of crude palm oil (scientifically known as
Compelling evidence from recent research prove that tocotrienols are detected at appreciable levels in the plasma after supplementation, whether this was done on a short-term or long-term basis [34]. While both compounds are basically bioavailable, tocotrienol has a shorter plasma half-life [33]. One study showed that the half-life of α-, γ- and δ-tocotrienols in human plasma was estimated to be 2.3, 4.4 and 4.3 hours respectively [35]. However, the half-life of α-tocopherol and γ-tocopherol was 57 and 13 hours respectively [36]. Given that tocotrienols are essentially oil-based compounds, and that emulsions are known to increase the absorption of oil-based compounds based on the new system of self-emulsifying drug delivery system [37], new products such as Tocovid Suprabio™ were developed following this technique. This new product led to a threefold increase in the peak plasma concentration of α-tocotrienol in humans compared to a previous study [38]. It has also been shown that the bioavailability of tocotrienols is dependent on several factors, food status being one of them. The mean apparent volume of tocotrienol distribution values is lower in the fed state, which means that the absorption is much better than in the fasting state [35]. Undoubtedly, tocotrienols have a very different pharmacokinetics from tocopherols which remain longer in the bloodstream. However, the biodistribution of tocotrienols pointed to the accumulation of the compound in the vital organs [34]. Therefore, tocotrienols would score high in terms of therapeutic efficacy since this requires not only bioavailability but also presence in the target organs.
One of the most well-known effects of vitamin E is its anti-oxidant capability in inhibiting the peroxidation of lipids after its incorporation into the cellular membranes [39]. It is well documented that tocotrienol scavenges the chain propagating the peroxyl radicals [39]. Indeed, α-tocotrienol has a much stronger anti-oxidant effect than α-tocopherol. This superiority is due to a more even distribution of α-tocotrienol in the plasma membrane as a result of a more efficient collision of α-tocotrienol with the radicals. Compared to tocopherols, tocotrienols also have a higher recycling efficiency thanks to their chromanoxyl radicals [39]. These anti-oxidant properties of tocotrienol have a lasting impact on health in general. For instance, patients with hyperlipidaemia and carotid stenosis have been shown to demonstrate a significant reduction in thiobarbituric-acid-reactive substances that were related to platelet peroxidation. It is also proven that tocotrienols have the ability to scavenge free radicals that cause DNA damage, hence providing protection especially to the older age group [40].
One of the most feared ailments is cardiovascular disease, and with 17.9 million deaths every year, the World Health Organization (WHO) considers it the main cause of death globally [41]. WHO estimated that out of five mortalities from cardiovascular diseases, four were caused by heart attacks and strokes, with almost a third of these deaths occurring in people less than 70 years of age [41]. Among the modifiable risk factors of atherosclerosis that cause heart attacks are hyperlipidaemia, hypertension, diabetes mellitus and thrombosis. Given its ability as a lipid-lowering, blood pressure-lowering, anti-diabetic and anti-thrombogenic agent, the effects of vitamin E – especially tocotrienol – deserve a thorough investigation.
Atherosclerosis is considered the most important event that leads to heart attack and stroke as a result of abnormal deposits of lipids, cholesterol and plaque build-up. Animal studies have been conducted in rabbits to look at the microscopic development of atherosclerosis and lipid peroxidation. After ten weeks of treatment with tocotrienol-rich fraction (TRF) which normally consists of 80% tocotrienol and 20% tocopherol, the researchers [42] found that the cholesterol-fed rabbits had a lower content of malondialdehyde (MDA) or modified low density lipoprotein – a diagnostic biochemical marker for atherosclerosis. The rabbits also had less intimal thickening, while their internal elastic lamina was better preserved compared to those fed on a normal diet. Another study [43] showed that atherosclerosis is prevented through the modulation of the peroxisome proliferator-activated receptors (PPAR) when TRF is administered. A different study [44] found that, after being given TRF, subjects undergoing chronic haemodialysis showed improvement in their high-density lipoprotein (HDL), triglycerides and total plasma cholesterol as compared to placebo. All these studies prove that TRF intake essentially improves the lipid profiles, thereby preventing atherosclerosis.
Another important issue is related to myocardial ischaemia reperfusion injury. This happens when blood flow is restored to an infarcted myocardium either via percutaneous transluminal coronary angioplasty or bypass surgery. Restoring the blood flow, a process known as reperfusion, could also cause injury to the heart muscles and is therefore termed as myocardial ischaemia reperfusion injury. Reperfusion injury could account for almost 50% of the final size of myocardial infarction [45]. Almost all isoforms of tocotrienol have been shown to have cardioprotective effect. Nonetheless, γ-tocotrienol is demonstrably the most potent in myocardial ischaemic injury model. This particular study [46] shows that the interaction between mitogen-activated protein kinase (MAPK) with caveolin and proteasome plays an important role in the cardioprotective effect of tocotrienol that is achieved by altering the availability of pro-survival and anti-survival proteins.
The discussion on this topic would be incomplete without any mention of thromboembolic events. In one animal study on dogs [47], an injection of intravenous tocotrienols and tocopherols was administered; it was noted that the cyclic flow that measures the acute platelet-mediated thrombus formation and collagen-induced platelet aggregation was significantly reduced in those receiving tocotrienol compared to those injected with tocopherol.
All these data suggest that tocotrienols provide better cardioprotective effect than tocopherols insofar as myocardial infarction, stroke or thrombosis is concerned.
Studies on the hypercholesterolaemic properties of tocotrienols have gained traction after it was shown that the addition of tocotrienols significantly lowered the cholesterol level [48]. This effect was mediated by the inhibition of HMG-CoA reductase by post-transcriptional suppression of the enzyme itself by tocotrienols [49]. Indeed, γ-tocotrienol has been observed to have a dramatic 30-fold activity in inhibiting HMG-CoA reductase [50]. A later study further indicated that the American Heart Association Step 1 diet and TRF25 (25–200 mg/day) from rice bran could reduce the total cholesterol, LDL, triglycerides, and also apolipoprotein B in hypercholesterolaemic patients [51]. Another study demonstrated that when 30 mg tocotrienols are mixed with 270 mg flavonoids, the total serum cholesterol level, LDL, triglycerides and apolipoprotein B are also reduced in hypercholesterolaemic patients [52]. Furthermore, hypercholesterolaemic patients with non-alcoholic fatty liver disease who were treated with mixed-tocotrienols showed a higher percentage of normal liver echogenic response [53]. A study on atherogenesis using human monocyte-macrophages showed that α-tocotrienol, like the new compound FeAOX-6 which combines both the anti-oxidant structural features of tocopherols and carotenoids, reduced the cholesterol accumulation in the cells, with α-tocotrienol having a more potent effect [54].
Diabetes mellitus – which has risen dramatically in all countries irrespective of their income levels – is a chronic metabolic disease characterised by elevated blood sugar level that could affect the eyes, kidneys and nerves in the long run. While Type II diabetes develops when the body becomes resistant to insulin, Type I diabetes arises when the pancreas produces less or no insulin at all. According to current WHO estimates, approximately 422 million people worldwide suffer from diabetes [55]. Indeed, about 1.6 million deaths are attributed to diabetes on a yearly basis [55]. Alarmingly, these dismal numbers have been growing steadily in the last few decades.
Studies on the antidiabetic effects of vitamin E were conducted as early as the 1990s to determine any possible association between vitamin E and diabetic risks [56, 57, 58] as well as the correlation between the dietary intake of vitamin E and insulin action [59, 60]. In a 2004 study with a very long follow-up, it was demonstrated that the intake of vitamin E reduces the risk of Type II diabetes onset [61]. It was also found that TRF reduces the total cholesterol level, low-density lipoprotein (LDL) and total plasma lipid in diabetic patients [62]. Patients who were given canola oil enriched with tocotrienol also showed a significant reduction in their urine microalbumin and the serum C-reactive protein (CRP) known for its protective effect on the kidney and against nitrosative stress [63]. In an animal model, it was observed that both TRF and α-tocopherol improved the vascular endothelial function in streptozotocin-induced diabetic rats through their sparing effect on endothelium derived nitric oxide bioavailability [64]. Another study determining the effects of TRF on erythrocyte membranes and leukocyte deoxyribonucleic acid (DNA) damage in streptozotocin-induced diabetic rats revealed that daily supplementation of tocotrienol for four weeks could inhibit lipid peroxidation while increasing the level of antioxidant markers [65]. In an animal study on the cognitive function and neuroinflammatory cascade in streptozotocin-induced diabetes, it was shown that the administration of tocotrienol significantly prevented behavioural, biochemical and molecular changes associated with diabetes. This points to the potential benefit of tocotrienol in preventing diabetic encephalopathy [66].
Diabetic nephropathy is a common complication of both Type I and Type II diabetes. Diabetic nephropathy (also called clinical nephropathy, proteinuria or microalbuminuria) is defined by the presence of protein of >0.5 g/24 h in the urine [67] and it increases the risk of death. In an animal study [68] designed to investigate the impact of tocotrienol in streptozotocin-induced diabetes in terms of renal function and reno-inflammatory cascade, it was found that tocotrienol has a more profound effect than tocopherol in preventing biochemical and molecular changes associated with diabetes [68]. It was concluded from the study [68] that tocotrienol modulates the release of pro-fibrolytic cytokines, apoptosis, the ongoing inflammation, and the associated oxidative stress, which confers a renoprotective effect on the kidneys. Another study [69] was designed to determine whether TRF from palm oil (PO) or rice bran oil (RBO) could improve the renal function of rats as a result of their hypoglycaemic and anti-oxidant effect. The results analysed the fasting blood glucose, glycosylated haemoglobin, renal function biological markers, and oxidative stress in the serum and urine of the rats. It was revealed that both palm-oil TRF (PO-TRF) and rice bran oil TRF (RBO-TRF) significantly improved renal function and glycaemic status, although PO-TRF conferred a better efficacy than RBO-TRF [68]. Hence, it was concluded that PO-TRF was more effective as a neuroprotective and hypoglycaemic agent compared to RBO-TRF [69]. Another study [70] revealed that TRF ameliorated lipid induced nephropathy in type-II diabetes by modulating the TGF-β – besides leveraging on its hypoglycaemic, hypolipidaemic and antioxidant properties – in order to prevent the increased expression of collagen type IV and fibrinogen. A recent prospective, randomized double-blind study [71] that was conducted to assess the effect of tocotrienol-rich vitamin E on diabetic nephropathy found that it attenuates the progression of diabetic nephropathy. It was also observed that a 12-week supplementation with tocotrienol-rich vitamin E led to a statistically significant improvement in renal function despite having no effect on glycaemia [71].
One of the most common complications of diabetes mellitus is diabetic retinopathy which could lead to blindness in severe cases [72]. It is estimated that the prevalence of diabetic retinopathy worldwide is about 35%, with approximately 10% of the world population afflicted with a vision-threatening disease [73, 74]. A strong correlation has been established between chronic hyperglycaemia and poor diabetic control with diabetic retinopathy [75]. Indeed, with the incidence of diabetes mellitus rising worldwide [76], a concomitant increase in diabetic retinopathy is to be expected [77]. A characteristic feature of diabetic retinopathy is retinal microvascular changes accompanied by an earlier neurodegeneration [78]. Oxidative stress, which induces hyperglycaemia, is considered as one of the main factors responsible for microvascular complication in diabetes mellitus [79]. Hyperglycaemia triggers cellular events resulting in inflammatory cytokines reactions that in turn accelerate microvascular changes [80]. Another important event is angiogenesis, an over-expression of vascular endothelial growth factor (VEGF) associated with neurodegeneration and diabetes-induced oxidative stress [81]. As mentioned earlier, antioxidants confer their benefit in oxidative stress-induced diseases, including diabetic retinopathy [82, 83], by scavenging free radicals through the hydrogen atom situated at the chromanol ring [84]. Indeed, a recent study [85] on streptozotocin-induced diabetic retinopathy in rats alluded to the beneficial effect of tocotrienol in preventing retinal neurodegenerative changes; it was shown that TRF prevented diabetic-induced changes in retinal layer thickness, retinal cell count, retinal cell apoptosis and retinal expression of VEGF.
One of the complications faced by almost 26% to 53% of diabetic patients worldwide is diabetic peripheral neuropathy [86, 87] that significantly impairs their quality of life [86]. The total cost of diabetic care [88] is around 4.2-fold higher among diabetic patients with neuropathic pain [89]. The mainstay treatment for managing diabetic neuropathy surely lies in glycaemic control and pain management [88]. To that end, various pharmacological agents [90, 91] have been used, but they are all limited either by their adverse effects or by having no effect at all on the pathway of the neuropathic pain [92]. It is believed that oxidative stress plays a role in the pathogenesis of peripheral neuropathy [93]. One animal study with diabetic rats has shown that neuropathic pain is reversed by tocotrienols via the modulation of oxidative-nitrosative stress, caspase-3, and inflammatory cytokine release [94]. Another prospective study [95] on human subjects was aimed at evaluating the protective effect of mixed tocotrienol on the white matter lesion (WML) that reflects neurodegenerative changes; it was shown that subjects who received 200 mg of mixed tocotrienols twice daily for two years have attenuated progression of WMLs compared to placebo [95]. However, a recent study by the investigators of the Vitamin E in Neuroprotective Study (VENUS) [96] found that the supplementation of oral mixed tocotrienols of 400 mg daily on diabetic patients with neuropathic pain did not show any remarkable improvement in alleviating the neuropathic symptoms. Nonetheless, the researchers qualified their statement by saying that their observation on the lancinating pain among the subsets of patients studied would require further exploration. More optimistically, a more recent randomized-controlled study [97] on the effects of tocotrienol on diabetic neuropathy showed that supplementation of tocotrienol-rich vitamin E of 200 mg twice daily led to a higher serum nerve growth factor (NGF) and improved the nerve conduction velocity for all nerves tested after eight weeks of supplementation. The researchers concluded that TRF could be a disease-modifying agent that targets the NGF in improving nerve conduction velocity [97].
Neurodegenerative diseases have been widely believed to be caused by oxidative damage due to reactive oxygen species [98]. Indeed, the increased levels of oxidative stress have been associated with numerous pathophysiological conditions together with derangements in mitochondrial complex I activity [99, 100]. Since vitamin E is a potent anti-oxidative agent, it is hypothesised that the neuroprotective effects of vitamin E is mediated via its anti-oxidative property [101]. A growing body of evidence supports the view that tocotrienol is a potent neuroprotective agent against Alzheimer’s disease [102]. However, as it stands today, the pathogenesis of Alzheimer’s disease remains unclear with a few different hypotheses [103]. Nonetheless, the ability of tocotrienol in reducing oxidative stress and promoting cellular repair contributes to its positive and beneficial effect in protecting the neurons. Admittedly, no clinical trials are available to support the hypothesis that tocotrienol could prevent Alzheimer’s disease, with available data based on only four human epidemiological studies [104, 105, 106, 107]. With more studies in the future, this research gap could certainly be narrowed. Figure 2 below summarizes the possible pathways for the neuroprotective actions of tocotrienol.
A summary of the current in vitro evidence of neuroprotective actions of tocotrienol. Legend: Solid line represents beneficial effects of tocotrienol on neurons. Dotted line represents potential adverse effects of tocotrienol on neurons.
Osteoporosis, a metabolic bone disease requiring extensive healthcare, is common in both men and women, though women suffer fragility fracture from osteoporosis at a ratio of 6:1 to men [108]. Osteoporosis is caused by an imbalance in bone remodelling, where the rate of bone resorption is faster than bone formation [109]. While it is known that menopause in women leads to oestrogen deficiency, in men, however, it is due to late-onset testosterone deficiency [110, 111]. The existing therapies for osteoporosis include bisphosphonates, teriparatide and strontium ranelate, all of which increase bone mineral density [112]. Recent studies have tried to explore the use of natural products to cure osteoporosis. With its inherent antioxidative and anti-inflammatory properties that are implicated in the pathogenesis of osteoporosis, tocotrienol is an agent of choice for such studies [113, 114]. Oxidative stress is known to damage osteoblasts by affecting both its differentiation and survival [115]. Oxidative stress also affects the signalling of osteoclasts and promotes the differentiation process [116]. Similarly, proinflammatory cytokines such as tumour necrosis factor (TNF), interleukin 1 (IL-1), and interleukin-6 (IL-6) promote osteoclasts differentiation [117]. The expression of proinflammatory cytokines is also suppressed by tocotrienol [118]. Hence, it is reasonable to assume that by reducing both oxidative stress and inflammation, the process of osteoporosis could be mitigated, if not prevented, by tocotrienol. A study on bone histomorphometry [119] that describes the bone volume and trabecular number, thickness and separation showed that palm tocotrienol preserved the trabecular bone structure, volume, and trabecular separation in rats with ovarian deficiency from ovariectomy. It was also demonstrated in another study [120] that in the bone loss model of rats, palm tocotrienol decreased the eroded surface and increased the osteoblast number, osteoid surface and osteoid volume in the supplemented study animal as compared to the other arm of the study. In another experiment on ovariectomised rats [121], the group that was treated with palm vitamin E showed significantly higher bone mineral density at the femur and vertebrae compared to the untreated group. The bone calcium level at the femur and vertebra of orchidectomised and ovariectomised was also found to be restored with palm vitamin E supplementation [122, 123]. Nonetheless, while tocotrienol has been proven to improve bone density and microarchitecture, and enhance bone biomechanical strength, the study [124] done was not convincing enough to show any statistical difference. The effects of tocotrienol on the bone are summarised below in Figure 3 [125].
The effects of tocotrienol on bone histomorphometry, bone mineral and bone calcium content.
Let us now look at the mechanism of actions of tocotrienol in the prevention of osteoporosis. Studies have revealed that oxidative stress plays a major role in the development of osteoporosis [126, 127]. Any increase in the oxidative stress process would lead to a decrease in differentiation of osteoclasts [128] as well as the bone resorption activity [129], which would subsequently impair the musculoskeletal system. Some in vivo studies [124, 130] which supplemented the study rats with tocotrienol showed a reduction in oxidative stress and anti-oxidant enzyme activities such as malondialdehyde. Additionally, an in vitro study [131] showed that γ-tocotrienol homologue decreased the oxidative damage on primary osteoblast culture. Tocotrienol exerts its effect by preserving the antioxidant enzyme activities in bone cells affected with oxidative stress [132]. Another effect is via the mevalonate pathway which is known to regulate osteoblastogenesis and osteoclastogenesis [133]. Tocotrienol suppresses the mevalonate pathway via the hydroxy-methyl-glutaryl-coenzyme A (HMG-CoA) reductase, an enzyme that is also involved in cholesterol synthesis [134]. Another study [135] further revealed that tocotrienol, in combination with statins, enhances bone static histomorphometry and remodeling markers in the ovariectomised rats although it could not be confirmed whether this was via the mevalonate pathway alone or if it involved some other pathways as well. The anti-inflammatory effect of tocotrienol in preventing proinflammatory cytokines such as IL-1 and IL-6 has also been shown to preserve bone health in rats [120, 136, 137]. It is worth noting that the differentiation and activity of osteoclasts and osteoblast are governed by some genes [138] and that supplementation of palm vitamin E has been shown to significantly enhance the gene expression [139]. Another study [140] demonstrated that tocotrienol could enhance the gene expression related to bone formation and osteoblast activity. All the above-mentioned studies confirmed that tocotrienol possesses some promising bone-protective effect: it increases the osteoblast number, mineral deposition and bone formation; and it reduces the osteoclast number, thereby preventing the bone resorption, erosion, and degeneration of bone mineral density and microarchitecture. The summary of the whole mechanism is illustrated in Figure 4 below.
The bone protective mechanism of Tocotrienol.
One of the most common autoimmune diseases is rheumatoid arthritis. With a prevalence of about 0.5 to 1.0% worldwide [141], it is presented as a typical systemic autoimmune disease of unknown aetiology that affects many joints [142]. The joint inflammation is characterised by some marked changes in the cartilage from the effects of proinflammatory mediators such as cytokines and C-reactive protein [143]. These include destruction of cartilage [144], leukocytes infiltration [145], and bone erosion [146]. The proinflammatory cytokines such as tumour necrosis factor-α (TNF-α), Interleukin-1α (IL-1α) and IL-1β [147] play a role in modulating inflammatory responses in the affected joints [148]. These cytokines have been shown to be involved in the pathogenesis of rheumatoid arthritis in animal studies. Since such studies closely mimic human disease [149], the development of biological agents that have the potential to modulate the cytokine mediators could yield an effective prevention against rheumatoid arthritis [150]. It has been demonstrated in an animal study [151] that palm γ-tocotrienol exerts an effect against both oxidative stress and joint pathology. In another study [152], it was discovered that palm δ-tocotrienol somehow reduced inflammation in arthritic rats. This should not be surprising given that palm tocotrienol has been shown to downregulate proinflammatory cytokines such as TNF-α, IL-1α, IL-β, IL-6 and IL-8 [153]. In another recent study [154] on the temporomandibular joint (TMJ) of a rat model, it was observed that in the group fed with TRF, the bone mineral density was notably increased. The researchers concluded that the concomitant decrease of plasma level of inflammatory cytokines with the increased bone density is sufficient evidence that TRF could be used in the management of TMJ rheumatoid arthritis.
It is also pertinent to look at another common ailment: bronchiole asthma. This chronic respiratory problem with a female preponderance afflicts more than 339 million people worldwide, according to a WHO estimate [155]. An increase in antinuclear antibodies and autoantibodies against bronchial epithelial antigens or endothelial antigens suggest that asthma is an autoimmune disease [156]. As the first experiment to demonstrate the effectiveness of tocotrienol in preventing asthma, a study [157] on rats showed that γ-tocotrienol possesses better free radical-neutralizing activity in vitro; reduces the eosinophil and neutrophil counts in vivo; and promotes lung-endogenous antioxidant activity. Another study investigated the effect of tocotrienol on airway remodelling [158], undoubtedly one of the characteristic features of asthma. It was shown that several inflammatory mediators were involved in airway remodelling [159, 160] and the most important among them is transforming growth factor beta1 TGF-β1 [161, 162]. The researchers convincingly proved the effect of γ-tocotrienol on the TGF-β1 induced differentiation of human airway smooth muscle and the extracellular deposition and the down-signaling of the airway smooth muscle cells activated by TGF-β1 [158]. This study suggested that γ-tocotrienol could play a therapeutic role in regulating airway remodelling in asthmatic patients.
Non-steroidal anti-inflammatory drugs (NSAIDs) are probably the most frequently used therapeutic agents in the world [163] for the treatment of pain, arthritis and trauma, besides many other indications. Achieving more than 73 million prescriptions per year [164], NSAIDs have been notoriously associated with gastrointestinal bleeding [165]. In an earlier study on a rat model of three different study groups [166], it was found that both TRF and tocopherol were equally effective in preventing aspirin-induced gastric ulcer. In another recent study [167] on a rat model comparing control to a group fed with omeprazole and another group with tocotrienol, it was discovered that while both groups were effective against gastric ulcer, the tocotrienol group displayed various modes in its protective effect – via the nitric oxide (NO) pathway and superoxide dismutase (SOD) activity – and in reducing TNF-α activity.
With the increasing adoption of radiation in both clinical and non-clinical applications [168], human exposure to radiation is set for an exponential increase. Radiation toxicity is manifested in oxidative stress and DNA damage [169], inflammatory changes [170] and cell apoptosis [171]. Studies were carried out to examine the potential benefits of naturally occurring products such as vitamin E, a potent anti-oxidant with the capacity to neutralize free radicals from radiation exposure by donating H atoms [172]. It was shown that exposure to ionizing radiation yields reactive oxygen species (ROS) and nitrogen species (RNS), hydroxyl radical, superoxide, peroxynitrite and hydrogen peroxide. These reactive species of ROS and RNS with radiation-induced radicals damage proteins, DNA and lipids, besides activating intracellular signalling pathways that release cytochrome C from the mitochondria, eventually leading to cell apoptosis [173, 174, 175]. Thanks to its potent anti-oxidant properties, tocotrienol has been a subject of several studies and has been reported to be radioprotective [176, 177, 178]. Studies on a rat model [176, 179] have showed the protective effect of γ-tocotrienol against radiation-induced DNA damage through the activation of haematopoietic progenitors, red and white blood cells including platelets, and also through the inhibition of 3-hydroxy-3-methylglutaryl-CoA Reductase (HMG-CoA Reductase) – a protein-coding gene-mediated nitrosative stress [180]. It is also proven that γ-tocotrienol increases serum IL-6 and granulocyte colony stimulating factor (G-CSF), both of which induce haematopoiesis and are protective against radiation-induced neutropenia and thrombocytopenia in mice [181].
Cancer (also known as malignant tumours or neoplasms) is the second leading cause of mortality globally according to WHO [182], with an estimated 9.6 million deaths in 2018. The cancer burden keeps on growing inexorably, exerting its pressure emotionally and financially on individuals and families, not to mention the community and health system. While chemotherapy has been the mainstay of treatment, it is limited by a few factors such as tumour immune evasion [183, 184], drug toxicity and resistance, and inappropriate cancer metabolism [185], all of which lead to possible metastases and recurrence. Hence the search for a more effective and potent anti-cancer agent. Buoyed by the earlier success in extracting anti-cancer agents from plants, the search has been on for a natural product. Tocotrienol became the choice of study due to its multitargeted actions in destroying cancer cells, promoting cancer cells apoptosis and inhibiting angiogenesis and metastases [186, 187, 188]. It is certainly beyond the scope of this writing to discuss all the research conducted on the effects of tocotrienol on cancer. Notable among the most recent research papers on this subject are “Tocotrienols and Cancer: From the State of Art to Promising Novel Patents” [189] and “Tocotrienols Modulate a Life or Death Decision in Cancers” [190]. For our purpose, it suffices to understand how tocotrienol exerts its anti-cancer effect. The mechanism of action is illustrated in Figure 5. Indeed, the effect of tocotrienol in suppressing the growth of different form of malignancies, including that of the uterine, ovary, prostate, liver, gastric, breast and brain, is well documented [191, 192]. Figure 5 below depicts the possible mechanism of actions of tocotrienols in exerting its anti-cancer effect [193].
Anti-cancer mechanism of actions of tocotrienol.
As an innate defence mechanism against cancer, apoptosis is considered critical [194, 195]. Natural molecules have the potential to exert their apoptosis-inducing quality [196, 197, 198, 199] and tocotrienols are one of those compounds that could exert the anti-neoplastic activity via this apoptosis mechanism [200]. One study [201] demonstrated that γ-tocotrienol caused substantial apoptosis in tumour cells by down-regulating several oncogenic gene products’ expression. It also displayed chemosensitisation and anti-invasive properties against prostate cells [202], and induced apoptosis in gastric cancer cells [203]. In another study [204], both α-tocopherol and γ-tocotrienol showed anti-proliferative activities and apoptosis on both the cervical carcinoma and hepatoma cell lines. Tocotrienols were also found to induce apoptosis in breast cancer cell lines [205] and effected both apoptosis and antiangiogenic activity of murine mammary cancer cells in mice [206]. A different study revealed that δ-tocotrienol is more efficacious than both α- and γ-tocotrienol in exerting its apoptosis effect on both human lung adenocarcinoma and glioblastoma [207]. In a study [208] on human bladder cancer cells, δ-tocotrienol was observed to have effectively induced apoptosis and chemosensitization, in addition to arresting the growth of human bladder cells. A study conducted on human chronic myeloid leukaemia cells [209] found that γ-tocotrienol was an effective inducer of apoptosis in the myeloid leukaemia cells. TRF mixture is also found to prevent cell proliferation, migration, and tumour cell invasiveness by inducing apoptosis in non-small cell lung cancer cells (NSCLC) [210]. Furthermore, γ-tocotrienol exerted its anti-proliferative effect and induced apoptosis in human cervical cancer cells [211].
Cell cycle has its checkpoints from one phase to another, and any aberrant activation may lead to the proliferation of tumour cells. Hence, it is imperative to target these checkpoints in cancer therapy [212]. The cell cycle and its checkpoints are illustrated in Figure 6 below [213].
The cell cycle and its checkpoints. There are four phases in the cell cycle – G1 phase, S-phase, G2-phase, and M-phase. The checkpoints control the progression of the cell cycle which is unidirectional in nature.
It is worthy of note that γ-tocotrienol had an effect on the G2/M arrest and apoptosis of breast cancer cells, with the potential to reverse multi-drug resistance [214]. Another study on brain cancer cells [215] documented the anti-proliferative effect of γ-tocotrienol in combination with another agent, jerantinine (an indole alkaloid obtained from leaves extract) which led to G0/G1 cell cycle arrest. The combination effect of γ-tocopherol and δ-tocotrienol was also cited in successfully arresting the G1 phase and G2/M phase in the cell cycle of prostate cancer cells [216], besides inhibiting prostate cancer cell growth. A synergistic effect was observed between δ-tocotrienol and geranylgeraniol (a compound synthesised endogenously in the human body via mevalonate pathway) in arresting G1 phase activity in prostate carcinoma cells [217]. With the addition of γ-tocotrienol, the cell cycle at G0/G1 phase was also arrested while the S phase was reduced in cervical cancer HeLa cells [211]. In short, tocotrienols, whether alone or in combination with other agents, are capable of exerting their inhibitory effects through the checkpoints in the cell cycle. This promising evidence supports their future development as therapeutic agents in modulating the checkpoints of the cell cycle.
Angiogenesis, defined as the formation of new blood vessels, is an important process for tumour growth and metastases [218] triggered by chemical signals from tumour cells. Researchers have identified more than a dozen angiogenic activators, including vascular endothelial growth factor (VEGF) which is a powerful angiogenic factor in neoplasms as well as normal tissue [219]. Therefore, targeting these angiogenic factors seemed to be the most rational intervention to combat tumour growth [220, 221]. Several trials [222, 223, 224] have shown the effectiveness of tocotrienol in inhibiting angiogenesis in various cancers, with the process illustrated in Figure 7 below [225].
The angiogenic cascade. (A) During the process of angiogenesis, stable vessels undergo (B) a vascular permeability increase which allows extravasation of plasma proteins. (C) Degradation of the ECM by matrix metalloproteases (MMPs) relieves pericyte-endothelial cells (EC) contacts and liberates extracellular matrix (ECM)-sequestered growth factors. (D) ECs then proliferate and migrate to their final destination and (E) assemble as lumen-bearing cords.
A study has shown that both δ- and γ-tocotrienol inhibit angiogenesis and proliferation in human hepatocellular carcinoma cells [226]. In another study, it was demonstrated that δ-tocotrienol inhibited tumour angiogenesis via VEGF and MMP-9 in pancreatic cancer cells; it also decreased the expression of cell surface markers in cancer stem cells [227]. Another study revealed that δ-tocotrienol exhibited potential against both melanoma and its associated stem cells [228, 229], while displaying suppressive action on prostate cancer stem-like cells [230]. Recent findings also indicated that tocotrienols displayed antiangiogenic protein expression of VEGF in colorectal cancer [231], malignant mesothelioma [232], breast cancer [233], ovarian carcinoma [234], and head and neck squamous cell carcinoma [235]. All these studies provide ample evidence of the role of tocotrienol in arresting tumour growth by inhibiting angiogenesis.
The morbidity and mortality from cancer are mainly caused by cancer metastases; in fact, almost 90% mortality is thought to be due to metastases [236]. Cancer metastasis starts at the primary tumour with the detachment of metastatic cells which then travel to different parts of the body either through the bloodstream or lymphatic drainage, and thereafter settle and start growing at the distal site [237]. To put it simply, the process of metastasis involves four essential steps: detachment, migration, invasion and adhesion. This is illustrated in Figure 8 below [238].
A schematic representation of the four stages of metastatic dissemination of cancer cells from the primary tumour into the blood circulation, involving detachment, migration, invasion and adhesion.
Cancer survival rate has improved significantly over the years from early diagnosis and inhibition of cancer growth. Nevertheless, the mainstay of cancer treatment for metastasis remains chemotherapy or radiotherapy. Tocotrienols have gained prominence in the last several years due to their anti-proliferative, anti-angiogenic, anti-migratory and anti-metastatic properties as exhibited in vivo and in vitro data [239]. Indeed, for metastasis to occur, cancer cells need to detach and migrate to a distant target organ, a process followed by adhesion and local invasion [240]. The ability of tocotrienol in halting cell migration has been demonstrated in several studies [224, 241, 242, 243]. In one study on human umbilical vein endothelial cells (HUVEC), treatment with δ-tocotrienol suppressed VEGF-induced migration by 50% [224]. Another study proved a dose-dependent inhibition of non-small cell lung cancer (NCSLC) cells migration [241], while a different one demonstrated the ability of γ-tocotrienol in inhibiting in-vitro human gastric cells migration [242]. In another study on VEGF-stimulated HUVEC migration essay, it was found that γ-tocotrienol suppressed the migratory potential of the HUVEC cells [243]. After the cancer cells migration, the subsequent event in the process of metastases is cell adhesion and invasion; this is preventable by suppressing the tumour cell invasion after adhesion [242]. An in vitro study has shown that after being treated with δ-tocotrienol, a pancreatic cancer mouse model no longer displayed any signs of invasive cancer [244]. A previous study has also showcased the ability of γ-tocotrienol in halting the invasion of the prostatic cancer cells in the control group [202], thereby suppressing the main process in the perpetuation of metastasis.
Oxidative stress refers to an imbalance of free radicals or reactive oxygen species (ROS) and antioxidants in the body [245]. This imbalance has been linked to a litany of chronic conditions including neurodegenerative disease, cardiovascular disease, diabetes mellitus, and many other pathologies such as cancer [246]. A variety of deleterious modifications of macromolecular components such as DNA, lipids and proteins were due to this chronic oxidative stress [247]. There is also a possibility that ROS mediates an indirect attack on DNA, resulting in secondary reactive intermediates that would couple with the DNA bases to form DNA adducts [248]. This formation is central to what is known as carcinogenesis [249]. Oxidative lesions have been implicated in the aetiology of cancer due to the oxidative DNA damage [250, 251, 252, 253, 254]. It is now clear how carcinogenesis is perpetuated by this oxidative stress process, as illustrated in Figure 9 below [255].
Oxidative stress mediating cancer development. Biological, chemical and physical factors mediated free radicals (ROS) which damage the biomolecules that initiate the neoplastic cells through the up-regulation of transcriptional factors and inactivation of tumour suppressor genes. They also alter the functions of DNA repair proteins, apoptotic modulators, metabolic enzymes and signalling pathways that induce the neoplastic condition.
Evidence from clinical and laboratory studies have showed that the elevated level of ROS contributed to both cancer initiation and cancer progression. Consequently, the most rational, if not preventive, approach is to use antioxidants for combating ROS [256]. Although the results regarding the use of dietary antioxidants were promising, research on this topic is still inconclusive and controversial [257]. Moreover, while studies have indicated that anti-oxidant supplementation resulted in an increase in survival rates and tumour response, with fewer toxicities than controls, a systematic review previously done on this topic showed no evidence of interference by antioxidants on chemotherapy mechanisms that conclusively proves that antioxidants (such as vitamin E) improve tumour response rate or the patients’ survival [258]. Despite promising results on improving the side effects from chemotherapy or radiotherapy treatment of cancer, further research into anti-oxidants [259], especially vitamin E in general and tocotrienol in particular, is highly warranted.
Long ignored despite being close yet superior to its related isomer tocopherol, tocotrienol is increasingly becoming a subject of interest in vitamin E research among the scientific community. One of the main reasons why it was understudied could be due to its abundant presence in palm oil, itself a much maligned product that had to bear the full brunt of a damaging smear campaign for decades. In fact, palm oil contains about 70% of all tocotrienol homologues namely α-, β-, δ- and γ-tocotrienols. Consequently, it would be no exaggeration to say that palm oil is nature’s best kept secret, if not the most promising natural substance in influencing health and disease.
Growing interest in tocotrienols has led to research exploring the molecular basis of their action in health. This chapter has highlighted the recent advances in this rapidly developing field of study. Indeed, recent studies have shown that tocotrienols may have superior chemopreventive or chemotherapeutic effects when used either alone or in combination with tocopherols. Indeed, tocotrienols are well adapted for their biochemical function. Thanks to their organic structure featuring a long-saturated carbon side-chain, they are able to penetrate more efficiently in the lipid membrane and in the intermembrane of tissues containing saturated fatty layers. This ability contributes immensely to their therapeutic efficacy.
Without doubt, the beneficial health effects of tocotrienols are partly related to their anti-oxidant activity. Though both tocotrienol and tocopherol have the ability to scavenge the free radicals directly by donating the phenolic hydrogen of their chromanol ring, tocotrienol is considered a better anti-oxidant due to its generally uniform distribution in the membrane bilayer coupled with a stronger disordering of its membrane lipid structure. Vitamin E, in particular tocotrienol, was shown to play a vital role in maintaining the integrity of the central nervous system through its anti-oxidant property. Indeed, as an organ with very high metabolic needs in terms of oxygen consumption, the brain is extremely susceptible to any forms of oxidative stress. However, current evidence is largely focused on Alzheimer’s disease – an age-related inflammatory neurodegenerative disease characterised by the presence of pathognomonic amyloid plaques and neurofibrillary tangles. It is postulated that the main mechanism of action of tocotrienol in attenuating the neurodegenerative changes is via its anti-oxidant action, either by inhibiting the production of ROS or by reducing the lipid peroxidation by-products. Admittedly, a gap still persists in this area insofar as other neurodegenerative conditions (such as Parkinson’s disease) are concerned. Notwithstanding the fact that some recent studies have reported contradicting outcomes on the relationship between tocotrienol and Parkinson’s disease, it is hoped that future studies will shed more light in this area.
Given the potential of tocotrienol in preventing auto-immune diseases, especially through its anti-inflammatory properties, the evidence available warrants further investigation into its molecular action. That would enable the development of drug targets to combat inflammatory diseases. Nevertheless, the therapeutic potential of tocotrienol as an anti-inflammatory agent cannot be denied. On the one hand, δ-tocotrienol somehow lessened joint inflammation in arthritic rats by reducing the level of proinflammatory cytokines. On the other hand, in a human study, γ-tocotrienol improved airway remodelling that characterises bronchiole asthma which is essentially an inflammatory disorder. Another rat model also showed that tocotrienol is effective against gastric ulcer. The gastroprotective effect of tocotrienol was mainly modulated through a reduction in inflammatory response, besides its anti-oxidative properties. Though this protective effect was witnessed in various animal models of gastric ulcer, clinical studies on the use of tocotrienol in patients with peptic ulcer disease or even gastritis are yet to be conducted.
As one of its health benefits, tocotrienol – through its ability to improve the lipid profiles – has been shown to confer a cardioprotective effect, at least with respect to atherosclerosis, myocardial infarction and thrombosis. There is sufficient evidence to prove that tocotrienol, especially in the form of γ-tocotrienol, is anti-cholesterolaemic; this is achieved by inhibiting the mevalonate pathway responsible for the synthesis of cholesterol and other isoprenoids. Overall, the potential of tocotrienol as a potential hypocholesterolaemic agent is evidenced by in-vitro, in-vivo and human clinical trials. Thus, tocotrienol supplementation is highly recommended for patients suffering from hypercholesterolaemia.
In fact, human studies on the effects of tocotrienol on cardiovascular disease have been limited to its anti-hypercholesterolaemic property. The only exception is an ongoing clinical study at the National Heart Institute of Kuala Lumpur, Malaysia. Conducted by this author, it investigates the ability of tocotrienol in preventing atrial fibrillation in post-coronary artery bypass grafting surgery. Indeed, while tocotrienol has been shown to be protective against cardiovascular disease in animal models, its direct effects on humans are inconsistent. Our current evidence serves as a basis for further clinical trials aimed at validating the positive effects of tocotrienol especially among patients susceptible to cardiovascular complications.
The potency of α-tocotrienol as an anti-atherogenic agent, besides being a bulwark against cerebrovascular disease, is well documented. Several animal models have demonstrated that tocotrienol protects against ischaemic stroke by attenuating brain lesion volume. A similar scenario was observed during clinical trials where it was shown to attenuate the progression of brain white matter lesion. Consequently, it could be safely concluded that tocotrienol protects against cerebrovascular disorders.
Tocotrinol-rich vitamin E (TRF) has been observed to ameliorate diabetes in animal studies through its superior antioxidant, anti-hyperglycaemic and anti-inflammatory properties. A recent clinical trial also showed that TRF significantly reduced serum creatinine level, and therefore has the potential to be used as a supplement in the treatment of diabetic nephropathy. Moreover, the anti-diabetic properties of tocotrienol in preventing nephropathy, retinopathy and neuropathy have been proven in several other studies.
Studies conducted on animal models have demonstrated that tocotrienol can mitigate, if not prevent, osteoporosis in rats by reducing oxidative stress and inflammation. Indeed, tocotrienol has been proposed to counter osteoporosis which leads to fragility fracture, a leading cause of morbidity and mortality worldwide. It is postulated that tocotrienol mediated bone protection via its anti-oxidant, anti-inflammatory, mevalonate suppression and gene-modulating properties. Despite strong evidence in animal models showing improved bone structure and strength after tocotrienol supplementation, limited human clinical trials on the effects of tocotrienol on bone health has been a serious impediment to its clinical use.
The role of γ-tocotrienol in protecting against radiation toxicity has been a subject of numerous animal studies, and the results are very promising. With the widespread use of ionising radiation in various non-clinical applications such as construction, sterilization of food products and engineering, exposure to radiation – whether intentional or unintentional – is very high. Studies have shown that γ-tocotrienol has a protective effect against radiation injury by increasing haematopoietic progenitors, neutrophils, platelets, white blood cells and reticulocytes. It has also been demonstrated that γ-tocotrienol protects against vascular injury by inhibiting HMG-CoA reductase. Since tocotrienols accumulate in the small intestine and colon at a higher level than tocopherols, they could protect the gastrointestinal tract from injury.
Last, but certainly not least, with cancer being one of the leading causes of death worldwide, the role of tocotrienol as an anti-cancer agent cannot be underestimated. Tocotrienol has been shown to modulate intracellular signalling pathways; it induces apoptosis and cell cycle arrest, and inhibits angiogenesis, cell proliferation and metastases. Compared to its isoform tocopherol, tocotrienol displayed superior activities in anti-cancer studies. Indeed, in a structural-activity relationship study, the chromanol ring and phytyl carbon tail played a major role in inducing cancer cell apoptosis. However, despite the abundance of cell and animal studies investigating the role of tocotrienol, evidence regarding its preventive effects on cancer remain inconclusive, with most trials still at the preliminary stage. Nonetheless, our improved understanding of the mechanism of actions of tocotrienol in the suppression of cancer cell growth by inhibiting proliferation, migration, and invasion should not be discounted; it will inform more targeted research into cancer therapy in the future.
This chapter has highlighted the wonders of tocotrienols which, thanks to their efficacy and safety profile, are attracting increased attention. Examining the latest research into tocotrienols, it has demonstrated the undeniable benefits of tocotrienols in conferring protection against cancer as well as a whole litany of diseases including cardiovascular, metabolic, autoimmune, bone and neurological diseases. Admittedly, many of the researches were conducted in the laboratory, with some preclinical trials translated into clinical trials. Nonetheless, it is hoped that more randomised clinical trials will be carried out on a global scale in the near future. From the vessels in the heart to neurons in the brain, tocotrienols have the extraordinary potential to be the future of vitamin E research.
The author is the recipient of HOVID the Malaysian Palm Oil Board research grant for his randomised controlled study on the ‘Prevention of Atrial Fibrillation after Coronary Artery Bypass Grafting Surgery using Tocotrienol-rich Vitamin E, Tocovid, derived from Palm Oil’ which is being conducted at the National Heart Institute (IJN), Kuala Lumpur. However, the funders had no role in the preparation of this manuscript. The author would like to express his gratitude to Imad Jihadi Ahmad Farouk for illustrating the diagrams, and Nageeb Gounjaria for proofreading and editing the manuscript.
Sepsis is defined as life-threatening condition caused by a dysregulated host response to infection, resulting in organ dysfunction while septic shock is circulatory, cellular, and metabolic abnormalities in septic patients, presenting as fluid-refractory hypotension requiring vasopressor therapy with associated tissue hypoperfusion [1]. Septic shock has high mortality rate and constitutes 20% of all global deaths [2]. Mortality associated with septic shock range from 24–41% [3, 4, 5, 6]. Increased morbidities and decreased functional status of septic shock patients after hospital discharge are major concerns and related to poor management [7]. Management of Septic shock include early recognition, source control with antibiotic and surgical intervention if needed, adequate perfusion and vital organ support including renal and respiratory support [8]. Patient in the early stage of septic shock required individualized fluid resuscitation and early administration of vasopressor to ensure tissue perfusion.
Progression of sepsis to septic shock occur very quickly and leads to hypoperfusion, end organ failure and death. Figure 1 summaries the pathophysiology of sepsis and septic shock [9, 10, 11]. Hemodynamic, clinical and laboratory indices could be used to determine the level of hypoperfusion and its response to resuscitation. Table 1 summaries the perfusion indices of and their targets during resuscitation.
Pathophysiology of sepsis and septic shock.
Index | Target |
---|---|
Heart Rate | 60–90 Beats per minute |
Mean arterial pressure MAP | ≥65 mmHg |
Diastolic arterial pressure (DAP) | ≥50 mmHg |
Skin examination | Normal color worminess |
Temperature | ≥ 36oC |
Capillary Refill Time (CRT) | < 3 seconds |
Urine Output (OUP) | ≥ 0.5 ml/kg/hour |
Central Venous Pressure (CVP) | < 6–8 mmHg in spontaneous breathing > 12–15 mmHg in ventilated patient |
Serum Lactate | < 2.2 mmol/L |
Indices of hypoperfusion and their targets.
Tachycardia is common sign of septic shock, and it predicts poor prognosis of septic shock patient. It is caused by stimulation of α- and β-adrenergic receptors increases in response to venodilattion and could be also related high temperature. Tachycardia is a sign impaired arterial tone [12]. It increases oxygen consumption, decreases diastolic filling and coronary perfusion, and increases arrhythmia [13]. Patients with septic shock and persistent tachycardia despite resuscitation measures has high mortality and morbidity rate [14].
Blood pressure is easy to measure and monitor. Blood pressure is determined by cardiac output, systemic vascular resistance, and arterioles pressure and coronary perfusion and heart flow depend upon diastolic arterial pressure (DAP) [15].
Hypotension reflects decrease cardiac output, but it could be a delayed sign of hypoperfusion, and its absence does not necessarily rule out hypoperfusion. Hypotension triggers resuscitation. Low diastolic arterial pressure, in septic shock indicates impaired arterial tone. Optimizing blood pressure is one of the goals of fluid resuscitation and associated with better outcome [16]. Prolonged hypotension, low mean arterial pressure (MAP) and DAP associated with high mortality in septic shock patient [17, 18]. Normal MAP and DAP should be targeted to improve survival of septic shock patients [15]. No evidence what the best target level of DBP is but common approach is to titrate vasopressors in septic shock to keep DAP ≥50 mmHg [19]. Resuscitation should target MAP of 65 mmHg per the septic shock guidelines [20]. Hypoperfusion may persist even when pressure is restored so personalization approach to target blood pressure should consider other indices of perfusion [21].
Skin examination including its color, blanching and worminess is one of the most important physical examination to determine level of skin perfusion which reflect vital organ perfusion. Anterior aspect of the knee is one body area that commonly examined for skin perfusion Mottling score is one of indices of hypoperfusion and associated with worse outcome regardless of vasopressor use [22, 23]. Normalization of skin color and disappearance of mottled skin are targets of resuscitation and related to higher survival rate of septic shock patient [24, 25].
Skin temperature is one of the most accessible markers of skin perfusion and hence tissue perfusion [26]. Hypothermia in circulatory shock is associated with impaired outcome [27].
CRT is the time taken to regain distal capillary bed color after blanching by pressure. Normally should be less than 3 seconds. It has been shown in in study of 783 critically ill patients that CRT is sensitive sign of decrease cardiac output measured by echocardiogram [28]. Capillary refill time is one of the best indices of adequate perfusion [29, 30]. And could be used as screening tool to predict sick patient that might need admission to critical care area. In one study, CRT and lactate are similar in predict survival [31]. In other study prolonged CRT associated with decrease perfusion of the liver, kidneys, gut and spleen [32]. CRT more than 4 seconds associated with higher mortality rate of septic shock patients [33]. In a randomized controlled study of septic shock patients with high lactate level but with a normal CRT had lower day-28 mortality when compared to prolonged CRT and high lactate level and survival of patients is higher with when resuscitation is guided by capillary refill time but not lactate levels [34]. When CRT used as index as optimal resuscitation it led to decrease mortality rate and should be used to guide fluid resuscitation in septic shock patient [34, 35, 36]. Septic shock patients failing to normalize their CRT after the first fluid bolus in ED had high mortality [37].
Passive Leg Raise (PLR) Can assist in identifying preload dependence. Utilization of the passive leg raise as index of resuscitation lead to reduce net fluid balance, acute kidney injury and pulmonary edema and may improve outcomes [38].
PLR became more popular and easier to use in different sitting including emergency department sitting [39].
By moving the patient from a semi-recumbent position, lowering the trunk and raising the patient’s legs to 45°, an amount of ~300 mL of blood is transferred to the ventricles, thereby increasing the cardiac preload. If CO increases of at least 10% compared to baseline, the patient is considered preload responsive, thus capable of displaying a CO increase following administration of fluid. The change in cardiac output changes in is measured by thermodilution, echocardiography, pulse contour analysis or pulse pressure variation. Passive leg rising is shifts venous blood from the legs to the intrathoracic compartment. This response can predict the response to a fluid challenge. Passive leg-raise test is accurate and has excellent sensitivity and specificity, for that it is recommended to determine fluid responsiveness [20, 40]. A meta-analysis of 21 studies and 991 adult patients showed that a 10% 2% increase in cardiac output with PLR predicted fluid responsiveness [41].
Oliguria which is urine output less than 0.5 ml/kg/hour is one of the main triggers for fluid challenges in septic shock patient [16]. Oliguria is one of signs of acute renal failure which is an independent risk factor associated with increased mortality during sepsis. Low UOP may reflect low renal perfusion pressure. UOP 30–50 mL/h in adult patient with septic shock should prompt further fluid resuscitation or other measures to increase cardiac output in a non–fluid-responsive patient [42]. UOP should not be taken alone as fluid resuscitation may not increase urinary output and cause positive fluid balance in patients with septic shock [20].
Venodilation and hypovolemia cause decrease in ventricular preload which is signaled by decrease in central venous pressure. CVP reflect the right atrial pressure [43]. CVP alone is a poor variable to predict fluid responsiveness [44, 45]. The target CVP is < 6–8 mmHg in spontaneous breathing patient and > 12–15 mmHg in mechanically ventilated patient [46].
Lactates reflect the onset of anaerobic metabolism. In experimental conditions, lactate increases when oxygen consumption increased and oxygen delivery decreased. Lactate also elevated in beta-adrenergic stimulation, leading to an accelerated glycolysis and liver failure. Lactate >2 mmol/L associated tissue hypoperfusion (lactate >2 mmol/L) [47]. Clinical studies show high lactate levels are associated with a high mortality, independently of its cause [48]. Lactate is easy to measure and can be used in emergency department triage and as a goal of early sepsis therapy [49]. Repeating lactate measurements is a trigger of resuscitation [20]. Lactate-guided resuscitation has emerged after the observation that the higher the decrease in lactate levels, the best the outcome [50].
Crystalloid intravenous fluid either ringer lactate or 0.9% normal saline is the first and the main step in restoring hemodynamic instability. Septic shock patient in the initial stage should be considered fluid responsive and receive fluid bolus [52]. Not all septic shock patient will respond to the initial fluid resuscitation, hence additional pharmaceutics intervention is needed to augment of fluid resuscitation to restore the hemodynamic and improve organ perfusion [53, 54]. Fast intravenous (IV) crystalloid infusion has a slower redistribution rate. Interstitial distribution is hypothesized to be greater in sepsis than in healthy volunteers due to sepsis pathophysiology [55] (Figure 1). The maximal effect of IV crystalloid bolus achieves at one minute and return to baseline after 30 minutes. Only one third of septic shock patient will have risen in MAP after fluid challenge [56, 57]. Amount of IV fluid resuscitation in patients with septic shock is not known. In one retrospective study found large amount of fluid more than 5 liter per day associated with increase mortality rate and need of ventilatory support [58, 59]. 50% 0f septic shock patients will be non-fluid responsive, where a condition where the administration of more fluid bolus may lead to fluid accumulation, impaired oxygen delivery, and worsening hypoperfusion [60]. How fast fluid should be administered in septic shock resuscitation is not known. Mainly retrospective studies shows failure to complete 30 mL/kg of IV crystalloid over 3 hours was associated with increased mortality [61]. In multi-center study found IV fluid administration within six hours was associated with decreased mortality [62]. regarding type of fluid in resuscitating septic shock patient, the current guideline recommends both sodium chloride and balanced crystalloids [20]. Studies within the critically ill have shown lower risk of in-hospital or 30-day mortality, AKI, or major adverse kidney event in the first 30 days with the use of balanced crystalloids over sodium chloride solutions [63, 64]. SMART trial, compared the two solutions in 15,802 critically ill patients, reported a lower rate of death from any cause, renal-replacement therapy, or renal failure with using balanced crystalloids versus normal saline [63]. In secondary analysis of SMART study among 1,641 patients were admitted to the medical ICU with a diagnosis of sepsis, balanced crystalloids was associated with a lower 30-day in-hospital mortality rate, renal failure, and a higher number of vasopressor free days compared with use of saline [64]. Amount of fluids resuscitation should be decided to minimize the complication of over resuscitation as pulmonary edema, brain edema, abdominal compartment syndrome and third space edema which will lead resulting in end-organ hypoperfusion by decrease oxygen delivery, capillary blood flow and lymphatic drainage. Which explain worse outcomes in shock with a positive fluid balance [55, 65, 66]. Collapsible inferior vena cava can along with other hypoperfusion indices can be used to monitor fluid and resuscitation of septic shock patient [67]. Resuscitation of septic shock patient with high volume of normal saline is associated with hyperchloremia, AKI, multiorgan dysfunction, and high mortality [68, 69]. Fixed amount of fluid hardly suitable for all septic shock patients, Teboul and Monnet proposed to administer crystalloid about 10 mL/kg within the first 30 to 60 min and monitor patient [52]. If patient develop any signs of respiratory failure stop further boluses. In case CRT is still prolonged, tachycardia or low blood pressure reading, skin mottling increase in the infusion rate [70].
Vasopressor increases systemic vascular resistance (SVR), cardiac output CO, and heart rate (HR) and rapidly restore organ perfusion [71]. Vasopressors either catecholamine- or non-catecholamine-based agents. Dopamine, norepinephrine, epinephrine, and phenylephrine are catecholamine-based vasopressors while vasopressin is a non-catecholamine-based vasopressors [72]. Norepinephrine is the first-line vasopressor for patients with septic shock [20]. Early vasopressors administration in septic shock patients revert the severely impaired arterial tone and associated with lowest mortality rate occurred when vasoactive agents were started 1 to 6 hours of septic shock identification [20, 73, 74, 75, 76]. CENSER trial shows early NE administration is associated with increased shock control over the first 6 hours [76]. Addition of vasopressin to norepinephrine in the few hours of shock when doses of norepinephrine dose is ≥1 μg/Kg/min, may decrease mortality, arrhythmia, hypotension and need for renal replacement therapy [77, 78]. Addition of vasopressin to norepinephrine is more effective in early septic shock management and reach MAP target faster and lower incidence of atrial fibrillation [79, 80]. Possible complication of vasopressor includes dysrhythmias tachycardia or atrial fibrillation. Hyperlactatemia and hyperglycemia [80, 81]. Peripheral administration of vasopressors includes extravasation and peripheral ischemia given their potent vasoconstrictive properties [82]. Extravasation was uncommon if vasopressors are administered peripherally for less than 22 hours. Peripheral administration of vasopressors in upper arm using 20 gauge or larger is safe and feasible in the initial hours of resuscitation [82, 83, 84]. Vasopressor treatment can be initiated on a peripheral venous line with non-invasive BP monitoring, and shifted, as soon as possible, to central venous catheter with arterial pressure monitoring [85].
Early norepinephrine administration should be started in septic shock patient with slow response to fluid resuscitation. Vasopressin is recommended in when norepinephrine dose is ≥1 μg/Kg/min.
Septic shock is life threatening condition complicated with hypoperfusion, Indices of hypoperfusion are combinations of pressure and flow measurements and clinical markers. Indices should be taken together and not to rely only on one index to diagnose and mange hypoperfusion. Perfusion indices should be used to individualize fluid administration approach in balanced crystalloid is recommended over normal slain in septic shock resuscitation. Early norepinephrine administration should be started in septic shock patient with slow response to fluid resuscitation. Vasopressin is recommended in when norepinephrine dose is ≥1 μg/Kg/min.
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Thus proteomics, an area of research that detects all protein forms expressed in an organism, including splice isoforms and post-translational modifications, is more suitable than genomics for a comprehensive understanding of the biochemical processes that govern life. The most common proteomics applications are currently in the clinical field for the identification, in a variety of biological matrices, of biomarkers for diagnosis and therapeutic intervention of disorders. From the comparison of proteomic profiles of control and disease or different physiological states, which may emerge, changes in protein expression can provide new insights into the roles played by some proteins in human pathologies. Understanding how proteins function and interact with each other is another goal of proteomics that makes this approach even more intriguing. Specialized technology and expertise are required to assess the proteome of any biological sample. Currently, proteomics relies mainly on mass spectrometry (MS) combined with electrophoretic (1 or 2-DE-MS) and/or chromatographic techniques (LC-MS/MS). MS is an excellent tool that has gained popularity in proteomics because of its ability to gather a complex body of information such as cataloging protein expression, identifying protein modification sites, and defining protein interactions. 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