Currently used definitions to describe nutraceuticals.
\\n\\n
Dr. Pletser’s experience includes 30 years of working with the European Space Agency as a Senior Physicist/Engineer and coordinating their parabolic flight campaigns, and he is the Guinness World Record holder for the most number of aircraft flown (12) in parabolas, personally logging more than 7,300 parabolas.
\\n\\nSeeing the 5,000th book published makes us at the same time proud, happy, humble, and grateful. This is a great opportunity to stop and celebrate what we have done so far, but is also an opportunity to engage even more, grow, and succeed. It wouldn't be possible to get here without the synergy of team members’ hard work and authors and editors who devote time and their expertise into Open Access book publishing with us.
\\n\\nOver these years, we have gone from pioneering the scientific Open Access book publishing field to being the world’s largest Open Access book publisher. Nonetheless, our vision has remained the same: to meet the challenges of making relevant knowledge available to the worldwide community under the Open Access model.
\\n\\nWe are excited about the present, and we look forward to sharing many more successes in the future.
\\n\\nThank you all for being part of the journey. 5,000 times thank you!
\\n\\nNow with 5,000 titles available Open Access, which one will you read next?
\\n\\nRead, share and download for free: https://www.intechopen.com/books
\\n\\n\\n\\n
\\n"}]',published:!0,mainMedia:null},components:[{type:"htmlEditorComponent",content:'
Preparation of Space Experiments edited by international leading expert Dr. Vladimir Pletser, Director of Space Training Operations at Blue Abyss is the 5,000th Open Access book published by IntechOpen and our milestone publication!
\n\n"This book presents some of the current trends in space microgravity research. The eleven chapters introduce various facets of space research in physical sciences, human physiology and technology developed using the microgravity environment not only to improve our fundamental understanding in these domains but also to adapt this new knowledge for application on earth." says the editor. Listen what else Dr. Pletser has to say...
\n\n\n\nDr. Pletser’s experience includes 30 years of working with the European Space Agency as a Senior Physicist/Engineer and coordinating their parabolic flight campaigns, and he is the Guinness World Record holder for the most number of aircraft flown (12) in parabolas, personally logging more than 7,300 parabolas.
\n\nSeeing the 5,000th book published makes us at the same time proud, happy, humble, and grateful. This is a great opportunity to stop and celebrate what we have done so far, but is also an opportunity to engage even more, grow, and succeed. It wouldn't be possible to get here without the synergy of team members’ hard work and authors and editors who devote time and their expertise into Open Access book publishing with us.
\n\nOver these years, we have gone from pioneering the scientific Open Access book publishing field to being the world’s largest Open Access book publisher. Nonetheless, our vision has remained the same: to meet the challenges of making relevant knowledge available to the worldwide community under the Open Access model.
\n\nWe are excited about the present, and we look forward to sharing many more successes in the future.
\n\nThank you all for being part of the journey. 5,000 times thank you!
\n\nNow with 5,000 titles available Open Access, which one will you read next?
\n\nRead, share and download for free: https://www.intechopen.com/books
\n\n\n\n
\n'}],latestNews:[{slug:"intechopen-signs-new-contract-with-cepiec-china-for-distribution-of-open-access-books-20210319",title:"IntechOpen Signs New Contract with CEPIEC, China for Distribution of Open Access Books"},{slug:"150-million-downloads-and-counting-20210316",title:"150 Million Downloads and Counting"},{slug:"intechopen-secures-indefinite-content-preservation-with-clockss-20210309",title:"IntechOpen Secures Indefinite Content Preservation with CLOCKSS"},{slug:"intechopen-expands-to-all-global-amazon-channels-with-full-catalog-of-books-20210308",title:"IntechOpen Expands to All Global Amazon Channels with Full Catalog of Books"},{slug:"stanford-university-identifies-top-2-scientists-over-1-000-are-intechopen-authors-and-editors-20210122",title:"Stanford University Identifies Top 2% Scientists, Over 1,000 are IntechOpen Authors and Editors"},{slug:"intechopen-authors-included-in-the-highly-cited-researchers-list-for-2020-20210121",title:"IntechOpen Authors Included in the Highly Cited Researchers List for 2020"},{slug:"intechopen-maintains-position-as-the-world-s-largest-oa-book-publisher-20201218",title:"IntechOpen Maintains Position as the World’s Largest OA Book Publisher"},{slug:"all-intechopen-books-available-on-perlego-20201215",title:"All IntechOpen Books Available on Perlego"}]},book:{item:{type:"book",id:"3696",leadTitle:null,fullTitle:"Aerial Vehicles",title:"Aerial Vehicles",subtitle:null,reviewType:"peer-reviewed",abstract:"This book contains 35 chapters written by experts in developing techniques for making aerial vehicles more intelligent, more reliable, more flexible in use, and safer in operation.It will also serve as an inspiration for further improvement of the design and application of aeral vehicles. The advanced techniques and research described here may also be applicable to other high-tech areas such as robotics, avionics, vetronics, and space.",isbn:null,printIsbn:"978-953-7619-41-1",pdfIsbn:"978-953-51-5741-0",doi:"10.5772/98",price:159,priceEur:175,priceUsd:205,slug:"aerial_vehicles",numberOfPages:780,isOpenForSubmission:!1,isInWos:1,hash:null,bookSignature:"Thanh Mung Lam",publishedDate:"January 1st 2009",coverURL:"https://cdn.intechopen.com/books/images_new/3696.jpg",numberOfDownloads:132090,numberOfWosCitations:124,numberOfCrossrefCitations:105,numberOfDimensionsCitations:162,hasAltmetrics:1,numberOfTotalCitations:391,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:null,dateEndSecondStepPublish:null,dateEndThirdStepPublish:null,dateEndFourthStepPublish:null,dateEndFifthStepPublish:null,currentStepOfPublishingProcess:1,indexedIn:"1,2,3,4,5,6,7",editedByType:"Edited by",kuFlag:!1,editors:[{id:"130793",title:"Prof.",name:"T. 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(René) van Paassen.",institutionString:null,position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"Delft University of Technology",institutionURL:null,country:{name:"Netherlands"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"1251",title:"Robotic Drones",slug:"robotic-drones"}],chapters:[{id:"5963",title:"Design and Development of a Fly-by-Wireless UAV Platform",doi:"10.5772/6464",slug:"design_and_development_of_a_fly-by-wireless_uav_platform",totalDownloads:4290,totalCrossrefCites:2,totalDimensionsCites:2,signatures:"Paulo Carvalhal, Cristina Santos, Manuel Ferreira, Luis Silva and Jose Afonso",downloadPdfUrl:"/chapter/pdf-download/5963",previewPdfUrl:"/chapter/pdf-preview/5963",authors:[null],corrections:null},{id:"5964",title:"Combining Occupancy Grids with a Polygonal Obstacle World Model for Autonomous Flights",doi:"10.5772/6465",slug:"combining_occupancy_grids_with_a_polygonal_obstacle_world_model_for_autonomous_flights",totalDownloads:3195,totalCrossrefCites:0,totalDimensionsCites:0,signatures:"Franz Andert and Lukas Goormann",downloadPdfUrl:"/chapter/pdf-download/5964",previewPdfUrl:"/chapter/pdf-preview/5964",authors:[null],corrections:null},{id:"5965",title:"Field Programmable Gate Array (FPGA) for Bio-Inspired Visuo-Motor Control Systems Applied to Micro-Air Vehicles",doi:"10.5772/6466",slug:"field_programmable_gate_array__fpga__for_bio-inspired_visuo-motor_control_systems_applied_to_micro-a",totalDownloads:3519,totalCrossrefCites:0,totalDimensionsCites:1,signatures:"Fabrice Aubepart, Julien Serres, Antoine Dilly, Franck Ruffier and Nicolas Franceschini",downloadPdfUrl:"/chapter/pdf-download/5965",previewPdfUrl:"/chapter/pdf-preview/5965",authors:[null],corrections:null},{id:"5966",title:"Advanced UAV Trajectory Generation: Planning and Guidance",doi:"10.5772/6467",slug:"advanced_uav_trajectory_generation__planning_and_guidance",totalDownloads:5461,totalCrossrefCites:5,totalDimensionsCites:6,signatures:"Antonio Barrientos, Pedro Gutierrez and Julian Colorado",downloadPdfUrl:"/chapter/pdf-download/5966",previewPdfUrl:"/chapter/pdf-preview/5966",authors:[null],corrections:null},{id:"5967",title:"Modelling and Control Prototyping of Unmanned Helicopters",doi:"10.5772/6468",slug:"modelling_and_control_prototyping_of_unmanned_helicopters",totalDownloads:3844,totalCrossrefCites:0,totalDimensionsCites:1,signatures:"Jaime del-Cerro, Antonio Barrientos and Alexander Martinez",downloadPdfUrl:"/chapter/pdf-download/5967",previewPdfUrl:"/chapter/pdf-preview/5967",authors:[null],corrections:null},{id:"5968",title:"Stabilization of Scale Model Vertical Take-off and Landing Vehicles without Velocity Measurements",doi:"10.5772/6469",slug:"stabilization_of_scale_model_vertical_take-off_and_landing_vehicles_without_velocity_measurements",totalDownloads:2411,totalCrossrefCites:0,totalDimensionsCites:0,signatures:"Bertrand Sylvain, Hamel Tarek and Piet-Lahanier Helene",downloadPdfUrl:"/chapter/pdf-download/5968",previewPdfUrl:"/chapter/pdf-preview/5968",authors:[null],corrections:null},{id:"5969",title:"Flight Control System Design Optimisation via Genetic Programming",doi:"10.5772/6470",slug:"flight_control_system_design_optimisation_via_genetic_programming",totalDownloads:3372,totalCrossrefCites:1,totalDimensionsCites:1,signatures:"Anna Bourmistrova and Sergey Khantsis",downloadPdfUrl:"/chapter/pdf-download/5969",previewPdfUrl:"/chapter/pdf-preview/5969",authors:[null],corrections:null},{id:"5970",title:"Fly-the-Camera Perspective: Control of a Remotely Operated Quadrotor UAV and Camera Unit",doi:"10.5772/6471",slug:"fly-the-camera_perspective__control_of_a_remotely_operated_quadrotor_uav_and_camera_unit",totalDownloads:4092,totalCrossrefCites:0,totalDimensionsCites:0,signatures:"DongBin Lee; Timothy C. 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From chapter submission and review, to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. 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Despite the great progress in understanding pathogenetic and pathological processes associated with Alzheimer’s disease (AD) in the last decade, the exact cause of AD still remains unrevealed. With the aim to clarify this cause, a number of hypotheses have been proposed, which involve, for example, the genetic hypothesis of AD based on malfunctioning variants of apolipoprotein E genes (
According to the amyloid hypothesis, slow accumulation of extracellular senile plaques, composed of Aβ deposits, occurs in the beginning and further progresses into AD. On the other hand, a direct link between the toxic influence of Aβ, the impaired neuronal functions and the decline in memory functions still has not been fully clarified, but it is broadly accepted that Aβ undoubtedly plays a key role in the neuropathology of AD [4].
\nAmyloid precursor protein (APP) is an integral membrane glycoprotein that is expressed in the brain and the central nervous system (CNS). APP can be cleaved by specific proteases in two different pathways: α-path and β-path [5]. In most cases, APP is cleaved in the α-path with the participation of enzymes α- and γ-secretases. The cleavage of APP by α-secretase proceeds in the way, which can be described as non-amyloidogenic one, while the cleavage in the β-way leads to formation of the toxic fragments of Aβ. In the case the non-amyloidogenic path, APP is cleaved by α-secretase to form a soluble extracellular fragment of sAPP-
Scheme of the amyloidogenic processing of APP.
Although APP is a part of the pathophysiological processes involved in AD, it is clear that the protein also carries out several natural physiological functions, particularly within the regulation of the synaptic transmission. It has been proved that transgenic mice with knock-out gene for APP exhibited an inability to transmit signals to the neuromuscular junction. Despite this fact, mice with upregulated expression of APP show better cognitive functions and spatial orientation. This is often rationalized by overproduction of AICD given by γ-secretase. The activity of APP is also put in a close connection with the metabolism of cholesterol. The neuroprotective character of APP was also demonstrated by suppression of the cyclin-dependent kinase 5 (CDK-5) activity in the process of tau hyperhosphorylation [9].
\nThe pathological role of APP is generally associated with the amyloidogenic way of its splitting. In general, many mutations of APP cause the autosomal dominant form of AD with early onset. Interestingly, genetic mutations in the adjacent part of the β-site of the APP gene induce neuroprotective effects, because Aβ is then produced only in a small extent. On the other hand, an excessive expression of the mutated APP forms associated with FAD (a redox cofactor in a number of biochemical reactions) leads to a loss of sense of smell, without dissemination of amyloid plaques, though. This observation is in a line with the loss of sense of smell, which occurs in some patients in the early stages of AD [9].
\nβ-secretase (BACE-1; also referred to as Asp2 or memapsin 2) is an enzyme that breaks down APP in the site called β into the
In order to clearly demonstrate the involvement of BACE-1 in the pathogenesis of AD, many prominent scientific groups worldwide dealt with developing a mouse model that had deactivated the gene for the production of BACE-1 (i.e., BACE-1 knockout (−/−) mice). At first, these strains of mice were viable, capable of reproduction, with the normal morphology of the body, without any obvious signs of damage of the tissues and normal blood picture [12]. This finding supported the idea that inhibition of BACE-1 can bring about the desired therapeutic effect without adverse effects. The results of this study also point to the fact that the related BACE-2 fails to offset the activity of BACE-1 in the formation of Aβ. It is interesting that hybridization of these BACE-1 knockout (−/−) mice with transgenic mice having the APP gene, which increasingly produce amyloid plaques, provided a generation, the newly born individuals of which did not exhibit the formation of Aβ, Aβ deposits or signs of memory impairment caused by production/accumulation of Aβ. As already mentioned, BACE-1 is located mostly in the presynaptic endings of neurons, where its physiological effects is assumed to occur. Over time, however, it was found that BACE-1 knockout (−/−) mice had impaired axonal conduction, experiencing hypomyelinization (i.e., disrupted formation of myelin, the substance that surrounds the axons and nerve fibers), memory disorders, disturbed neurochemical balance, pathological neurogenesis, astrogenesis, degeneration of neurons with increasing age, pathological changes in the retina and schizophrenic symptoms. All these discoveries observed in BACE-1 knockout (−/−) mice can serve as a model that reflects the potential adverse effects associated with the administration of BACE-1 inhibitors for normal animals or people [13].
\nThe substrates subject to proteolysis by BACE-1 are in particular the membrane-bound proteins like APP. Many of these BACE-1 substrates undergo a process called ectodomain shedding (ectodomain is a part of a membrane protein which protrudes to the extracellular space), while at the same time, these substrates can be cleaved by proteases, called also disintegrins, and ADAM-related metaloproteases. The extent of cleavage of the substrate by ADAM related proteases or BACE-1 depends on the nature of the particular substrate. All the possible side effects caused by inhibition of BACE-1 thus may not be always exhibited, assuming that some substrates are hydrolyzed by another protease [14].
\nThe homology between BACE-1 and BACE-2 gave rise to arguments that BACE-1 inhibitors may simultaneously inhibit non-selectively also BACE-2. For this reason, transgenic BACE-2 knockout (−/−) mice were developed to clarify the physiological role of BACE-2 and to explore the benefits offered by inhibition of this enzyme. Similar to the BACE-1 knockout (−/−) mice, the BACE-2 knockout (−/−) mice showed the same phenotype. Double-knockout mice, that is, mice with deactivated genes for BACE-1 (−/−) as well as for BACE-2 (−/−), are not phenotypically very different from mice without the gene for the BACE-1, with the exception of an increased number of dying mice freshly after birth. The results of this study therefore assume that nonselective inhibitors of both subtypes of the enzyme BACE may be well tolerated at least from the perspective of the inhibition of BACE-2. The latest research has shown that BACE-2 is expressed in the pancreatic β cells and BACE-2 knockout mice exhibit an improved glycemic regulation due to the increased production of insulin. These findings imply the possible use of BACE-2 inhibitors for the treatment of diabetes mellitus of type 2 [15].
\nCurrently, BACE-1 inhibitors have an exclusive position regarding the therapeutic options for introduction into clinical practice to treat AD [16]. Their mechanism of action is based on reducing the levels of Aβ in the brain. Although several of these inhibitors had already reached clinical testing, there are still important questions to answer, for instance, about their safety, the optimum degree of inhibition of BACE-1 needed to achieve the desired therapeutic effect without the presence of side effects, and the stage of the disease when these compounds are to be indicated in order to achieve the greatest assets [17].
\nAβ is produced by neurons in the brain, partly also by astrocytes and other glial cells, which are involved in the formation of this protein in particular during the stress conditions accompanying the AD development. For the production of Aβ, the activity of both enzymes, BACE-1 and γ-secretase, is necessary [10]. The biochemical processes involving the activity of these enzymes are often referred in the literature as the amyloid pathway. Importantly, modulation or inhibition of these enzymes can reduce the formation of Aβ in the brain of patients with AD. On the other hand, activation of the non-amyloidogenic pathway by supporting the α-secretase activity may also reduce the formation of Aβ and currently it is alternatively considered as a promising approach for therapy of AD. An important role for the accumulation of Aβ is also played by the genetic aspects of AD. Nowadays, more than 200 autosomal-dominant mutations in APP and presenilin (PS) have been identified which contribute to the occurrence of familial forms of AD [18]. Without any exception, all these mutations increase the production of all Aβ isoforms, in particular the toxic Aβ containing 42 amino acids (Aβ1–42). An example might be seen in Swedish mutation of APP in the amino acids Lys670 and Met671, that is, the places where BACE-1 enzyme cleaves APP. This mutation results in higher proteolytic efficacy of BACE-1, which promotes an increased rate of the C99 fragment formation and thereby the total production of Aβ [19]. The
Extensive research is dedicated to the development of small molecule inhibitors of BACE-1, capable to act centrally. The first experimental inhibitors were derived from short fragments of APP, being therefore peptide derivatives. These differed from APP by modified amino acid sequence and increased metabolic resistance against cleaving by BACE-1. In
The latest generations of BACE-1 inhibitors are characterized by a good capacity to permeate through the blood-brain barrier, by a suitable pharmacokinetic profile, and the ability to induce reduction of the cerebral levels of Aβ. The result of the research is a panel of several inhibitors of BACE-1, which have entered various stages of clinical testing [23].
\nIn 2012, the results of the first phase of clinical trials with inhibitor MK-8931 were presented (Figure 2), which had been performed in 88 healthy individuals aged between 18 and 45 years. The safety, tolerability, pharmacokinetic and pharmacodynamic parameters after single or repeated administration were experimentally determined. MK-8931 was generally well tolerated, and no severe side effects were observed. The main goal in this first phase was to determine whether MK-8931 was capable of penetration into the brain to inhibit the activity of BACE-1. Biomarkers monitoring the levels of Aβ1–40, Aβ1–42 and soluble fragment of APP (sAPP-β), which is formed by BACE-1, were intensively studied. MK-8931 significantly decreased the concentrations of cerebrospinal Aβ, depending on the dose administered, and even in repeated oral administration a reduction of Aβ in the CSF of up to about 90% has been observed. The plasma half-life of MK-8931 after a single administration was around 20 h, which assumes the dosing schedule within the range of a single daily dose. This was followed by a clinical study 1b, where the safety, tolerability, pharmacokinetics and pharmacodynamics in 32 patients with mild to moderate dementia of the AD type were determined. MK-8931 was applied in three different doses (12, 40 or 60 mg) and the effect was compared with the placebo over a period of 7 days. The markers of Aβ1–40, Aβ1–42 and sAPP-β were also monitored. As in the previous phase, decrease in the levels of Aβ, depending on the dose of the drug (for the Aβ1–40 57% (12 mg), 79% (40 mg), 84% (60 mg)) was observed and, in addition, without the presence of the more serious side effects. The results of this phase of clinical trials are especially important because the pharmacokinetic and pharmacodynamic properties of this BACE-1 inhibitor are not affected by the quantity of Aβ present in the brain of patients with AD. At the end of 2012, MK-8931 advanced to the clinical phase (II/III) with patients suffering from mild to moderate dementia of AD type. This substance was administered in dosages of 12, 40 and 60 mg and controlled with placebo in the total sample of 200 patients. According to the initial promising results, extension of the third phase of clinical trials by another 1960 patients with AD is expected. Further evaluation of MK-8931 is simultaneously monitored within the III phase of clinical testing on 1500 patients with AD. The results of both studies are to be expected in 2017–2018 [24].
\nChemical structures of BACE-1 inhibitors in clinical testing.
A non-peptidic BACE-1 inhibitor LY2811376 (Figure 2), which was analyzed in a study with oral administration, demonstrated satisfactory pharmacokinetic and pharmacodynamic properties in animal models, which promoted the compound to the first phase of clinical trials. These clinical studies, however, were soon discontinued due to adverse reactions, in particular in the area of inflammation of the retina and the occurrence of stroke. Although all other studies with the substance faded away, at present, LY2811376 has become a lead structure, which could be administered orally and reach its biological target behind the blood-brain barrier.
\nThe molecule marked with LY2886721 (Figure 2) represents the next evolutionary generation of orally acting BACE-1 inhibitors, which has entered into the second phase of clinical trials. Compared to its predecessor LY2811376, the novel drug LY2886721 did not exhibit any side effects in the area of the retina and any stroke. During the first phase of clinical trials on 47 healthy volunteers, no adverse effects were observed in 14 days (different dosing schemes—repeated administration of 5, 15 and 35 or 70 mg single administration). The biological half-life fluctuated around 12 h, allowing the dosing once per day, when the drug holds the necessary biological effect even after substantial elimination from the body. Treatment with LY2886721 resulted in the reduction of the plasma and cerebrospinal levels of Aβ1–40 by up to 74% (i.e., after the highest dose of 70 mg). Similar decreasing changes were detected in the cerebrospinal levels of Aβ1–42 and sAPP-β, while the blood level of sAPP-
The second phase of clinical trials with LY2886721 was carried out in 130 patients with moderate to severe AD dementia type. This testing, however, was terminated because of liver abnormalities, but, presumably, this is not associated with inhibition of BACE-1 [25].
\nE2609 (Figure 2) is an orally available, nonpeptidic spirocyclic inhibitor of BACE-1, which induced a significant decline of brain levels of Aβ in preclinical studies. Based on this success, E2609 entered the first phase of clinical testing in which 73 volunteers, administered uniformly with increasing dose from 5 to 800 mg of the drug, and 50 volunteers, administered with different doses in the range of 25–400 mg, participated. The plasma half-life of E2609 is around 12–16 h, which again allows one-day dosing schedule. At the maximal single dose (400 mg), decrease of the cerebrospinal Aβ levels by up to 85% has been observed. The concentration of sAPP-β has been similarly reduced, while sAPP-
γ-Secretase is a member of aspartic protease family that cleaves glycoproteins of type I including APP. Unlike β-secretase, γ-secretase has a regulated intramembrane proteolytic activity (RIP), thus, it breaks down domains inside of the cytoplasmic membrane. It is known that it breaks down multiple substrates, and to this day more than 50 such substrates, including APP, have been identified. Among these substrates are Notch, Jagged and Nectin-1α. The signal transmission by RIP is implemented so that the released intracellular domain is moved into the nucleus, as it is in the case of Notch, which regulates specific gene expression. Notch is therefore cleaved to Notch intracellular domain, NICD, which causes in the nucleus the mentioned regulation. In relation to AD, this signal pathway is interesting from the perspective of development and function of the nervous tissue.
\nOver the last few years, it has turned out that four main factors are responsible for the enzymatic activity of γ-secretase complex: presenilin, anterior pharynx-defective, presenilin enhancer 2 and nicastrin, which are described further in this chapter [27].
\nIn recent years, a series of potential inhibitors of γ-secretase has been designed and synthesized. Unfortunately, most of them are not specific to cleaving APP with γ-secretase, and, like in the case of BACE-1, they prevent processing of other γ-secretase substrates that do not have any or at least no obvious role in the pathogenesis of AD. For these reasons, the inhibition of γ-secretase has been associated with serious side effects, which adumbrated the end for most drug candidates in clinical testing.
\nHistorically, the first inhibitor of γ-secretase that underwent clinical studies was BMS-299897 (Figure 3) compound prepared by Bristol-Myers Squibb. In 2001, clinical trials of this molecule began, but the results of this study have never been fully described. We only know that the next clinical trials have been terminated.
\nInhibitors of γ-secretase in various stages of clinical testing.
Six other inhibitors of γ-secretase are currently in various stages of clinical testing involving patients suffering from AD. As for the compounds LY-450139, MK-0752, BMS-708163, PF-3084014, GSI-953 and ELND-006, animal studies indicated that these substances reduced the brain levels of Aβ after oral or parenteral administration (Figure 3) [28].
\nLY-450139 (Figure 3), also known as semagacestat, is an inhibitor of γ-secretase developed by Eli-Lilly. It is a derivative of benzoazepinone with triple selectivity to inhibit the cleavage of APP with respect to the cleavage of Notch (APP: IC50 = 15 nM and Notch: EC50 = 49 nM). This derivative has undergone all three phases of clinical trials. When tested on experimental animals, it was found that LY-450139 has an effect on the level of Aβ in the brain, cerebrospinal fluid (CSF) and the plasma in mice, guinea pigs and dogs. A similar positive effect was achieved in the cerebrospinal fluid (CSF) of AD sufferers. However, due to the neurotoxicity detected in transgenic mice, gastrointestinal problems and an increased risk of developing skin cancer in humans, clinical testing was abandoned [29, 30].
\nThis substance developed by Merck is a non-selective inhibitor of APP and Notch formation. In healthy volunteers, MK-0752 (Figure 3) administration led to reduction of Aβ1–40 levels in the CSF. However, the drawback was the mentioned non-selectivity toward Notch cleavage and significant toxicity in humans. MK-0752 has reached only the first phase of clinical testing [31].
\nThe drug E2012 (Figure 3) was developed by Eisai in cooperation with Torrey-Pines Therapeutics with the aim to reduce the levels of Aβ by modulating the γ-secretase without affecting the Notch. In mid-2006, the first phase of clinical testing has started, but in February 2007 it has been suspended due to the lenticular opacity observed in preclinical studies with rats. In the time of the study suspension, however, no health problems in humans were observed. In addition, the lenticular opacity has not appeared in later studies in monkeys. During a subsequent study, no eye toxicity was observed in rats, and, thus, the suspension of testing was repealed in April 2008. Currently, the drug is no longer the subject of research interests, anyway [32].
\nThe drug identified as BMS-708163 (Figure 3) is a benzene sulfonamide developed by Bristol-Myers Squibb. This molecule exhibits nearly 200× lower selectivity to Notch cleavage (Aβ1–40: IC50 = 0.3 nM and Notch: EC50 = 58 nM). Animal studies, specifically in rats and dogs, have shown the ability of BMS-708163 to reduce the levels of Aβ in the brain and the CSF without the Notch-related gastrointestinal and lymphoid toxicity. Despite the fact that reduction of the Aβ level in the CSF has been observed in healthy volunteers, there is insufficient information on storing Aβ plaques in the brain of transgenic mice, as well as on their behavioral changes. This inhibitor has passed the phase II of clinical development, but further testing is currently not being performed [33].
\nPF-3084014 (Figure 3) is a new effective, aminotetraline based γ-secretase inhibitor developed by Pfizer, which does not affect Notch. In in vitro tests, the compound was evaluated as an uncompetitive and reversible inhibitor of human γ-secretase with IC50 = 6.2 nM. In studies on tissue cultures, it seems as a weak inhibitor of Notch with IC50 = 1915 nM. The ratio between the APP and Notch selectivity is roughly 1500. The merit of this compound is a sufficient penetration through the blood-brain barrier, long-term effect on reducing the Aβ levels and no rebound phenomenon for levels of Aβ in animal plasma. As in the case of BMS-708163, there is also a lack of data for this inhibitor about the storage of Aβ plaques in transgenic mice, as well as about their behavioral processes. PF-3084014 is currently introduced into the second phase of clinical testing [34].
\nThis inhibitor, known also as begacestat, is a potent thiophene-related sulfonamide developed by Weyth. It is able to suppress the production of Aβ in low nanomolar concentrations in vitro (IC50 = 8 nM) and in vivo (Aβ1–42: IC50 = 15 nM). Cellular studies on the Notch cleavage showed 15× higher selectivity of this molecule to inhibit preferably the cleavage of APP. It was found that GSI-953 (Figure 3) improves the memory functions in transgenic mice; however, it does not diminish the level of Aβ1-40 in the CSF in people suffering from AD. This drug completed the first phase of the clinical trials, but the lack of its efficacy caused it to no longer be a subject of follow-up studies [35].
\nThe inhibitor ELND-006 (Figure 3) developed by Elan Pharmaceuticals shows increased selectivity for inhibition of the APP cleavage (IC50 = 0.34 nM) with regard to Notch cleavage (IC50 = 5.3 nM). Therefore, it does not significantly affect Notch; it has a good penetration through the blood-brain barrier and can reduce the level of Aβ in the brain in transgenic mice. The disadvantage of this drug is the rebound phenomenon in the plasma of animals and lack of data on behavioral processes in animal models of AD. Clinical studies of the drug have been terminated because of severe hepatic adverse reactions, which presumably are not related to the mechanism of γ-secretase inhibition by the drug [36].
\nPresenilins (PSs) are membrane proteins encoded by two genes: PS1 and PS2. PS, nicastrin, anterior pharynx-defective (aph-1) and presenilin enhancer 2 (pen-2) form an active part of the γ-secretase complex, while PS form the catalytic core of the complex [18].
\nPresenilin-1 (PS1) and presenilin-2 (PS2) are considered as the key elements of the γ-secretase complex. The proteins are composed of 9 transmembrane domains containing 467 or 448 amino acids. These domains are autoproteolytically cleaved in the process endoproteolysis to form two ends, each of them having an active aspartate site, which create the catalytic γ-secretase complex site for Aβ. Anterior pharynx-defective (Aph-1) and presenilin enhancer 2 (Pen-2) act as cofactors in the active γ-secretase complex. Aph-1 is a transmembrane protein composed of seven subunits with
Nicastrin has been described as the main protein that interacts with presenilins. This part of the γ-secretase complex contains 709 amino acids including glycoprotein with 1 large ektodomain and can serve as the substrate receptor of γ-secretase. Nicastrin is essential for the recognition and processing of the substrate, for the maturation of the γ-secretase complex and its transport to the cell surface [38].
\nIn addition to the amyloidogenic fragment of APP (i.e., sAPPβ), γ-secretase breaks down also a variety of other transmembrane proteins (e.g. Notch). Mutation in PS1 often leads to an increase in the relative production of toxic Aβ1–42 peptide, which is hydrophobic and is easily prone to aggregation. This process results in a cascade of pathological events, at the end of which a degenerative damage to neurons comes up. The hypothesis about the influence of PS1 mutations on the creation and subsequent aggregation of Aβ1–42 was supported by the results of studies on transgenic mice with an increased production of APP, in which increased formation and accelerated storage of the Aβ deposits occurred. Moreover, the PS mutations always appear in different parts of the protein, so it can be hard to predict what toxic effect due to PS mutation will show up. In this context, however, it is possible that the loss of normal functions of the PS caused by one of the mutations closely correlates with the onset of pathological cascades leading to AD.
\nThe most recent studies have pointed to the loss of function of PS, which is usually associated with the mechanism of AD development. In this respect, it was proved that mice with the knockout genes for both PS proteins exhibit degenerative disruption of the front part of the brain, without the formation and storage of Aβ, although cognitive dysfunctions arise as it is normally observed in AD with the appearance of Aβ in the brain. Similar symptoms can be found in frontotemporal dementia in humans, which is presumably caused by a mutation of the gene for PS1, when amyloidogenesis (i.e., formation of Aβ) does not occur. From the abovementioned information, it follows that neurodegeneration may proceed even without the formation of Aβ [39].
\nHowever, PS also plays an important role in many other physiological processes. These processes can be divided into those related with the activity of γ-secretase and those without a close connection with the activity of γ-secretase. It is interesting that some of the inhibitors of γ-secretase increase the production of Aβ1–42 in low concentrations while reducing the formation of Aβ1–40. A similar effect can be observed as a result of PS mutations [40].
\nApolipoprotein (APO) is a general term for denoting proteins which bind with lipids. They play an important role in the regulation of pathological manifestations caused by Aβ. APOE is the main representative of the APO present in the CNS, which is produced and secreted exclusively by astrocytes and microglia. APOE is involved in the transport of lipids between the cells in the CNS, where it physiologically induces the lipid homeostasis, repairs damaged neurons, supports synaptic transmission of excitation and separates specific toxins. The
A number of studies show that Aβ plays a key role in the onset and progression of AD. But so far, it is still not clear whether the culprit of the onset of dementia is the soluble or insoluble form of Aβ and if the extent of the Aβ impact depends on the localization of this protein in extracellular or intracellular compartments. Current research has revealed a variety of processes in which Aβ plays an important role, for instance, mitochondrial dysfunction, oxidative stress, turmoil and disruption of the transfer function of the membrane. According to the amyloid hypothesis, deposition of Aβ in the brain is the primary cause and controlling force of the degeneration associated with AD, which involves formation of intracellular neurofibrillary tangles and induce the death of neurons [42].
\nAD is a complex neurodegenerative disease which is caused by a number of factors, both biological and environmental. Among these factors, one of the main elements is excessive production of Aβ via amyloidogenic processing of APP, and its subsequent storage in the brain. All of these processes lead to neuronal death, which initializes the outbreak of dementia and AD with the early onset or sporadic forms with the late start. The genes encoding APP, BACE-1, PS1/2 and
This work has been supported by the MH CZ-DRO (University Hospital Hradec Kralove, No. 00179906) and by the grant of the Grant Agency of the Czech Republic No. 16-08554S).
\nPain occurs in all demographics, with a higher prevalence in some clusters (such as the elderly) and can be either acute or chronic [1, 2]. Chronic pain is a complex interplay between biology and psychology, where the intensity/magnitude differs depending on personal, sensory, emotional experience and persists more than 3 months beyond “normal” healing time [3, 4]. This type of pain affects more than 1.5 billion people worldwide [5] and has an estimated prevalence ranging between 17-27% [6, 7, 8, 9]. Chronic pain represents a significant financial burden that exceeds €300 trillion (approximately 1.5%-3% of the gross domestic product across the European Union) and up to $635 billion in the United States [10, 11]. According to the International Association for the Study of Pain (IASP), the main overarching categories of chronic pain are primary (such as fibromyalgia) and secondary pain (the focus of this chapter). Secondary chronic pain is further divided into six distinct categories: cancer-related pain, postsurgical or posttraumatic pain, secondary headache/orofacial pain, secondary visceral pain, and secondary musculoskeletal pain [12, 13].
\nMost chronic pain begins with the occurrence of an acute injury event resulting in pain that if left untreated can develop chronically into a pathological condition and can increase the risk of future deleterious health issues such as sleep deficiency, delayed wound healing, immune dysfunction, cardiovascular problems (related to the stress response) and respiratory problems (such as pneumonia; [14, 15]). Persistent, unrelieved pain can negatively impact quality of life, daily functioning, sleep quality, work productivity and is associated with a substantial personal economic burden [16].
\nPathologic pain is associated with multiple maladaptations in the nervous, endocrine, and immune systems [17, 18, 19] that often presents at multiple sites [20] and can be classified into nociceptive (somatic and visceral), neuropathic, nociplastic, or mixed [21]. Nociplastic describes pain of unknown origin that arises from altered nociception, despite no clear evidence of actual or threatened tissue damage that causes activation of peripheral nociceptors, evidence of disease or lesion of the somatosensory system causing the pain, such as early (pre structural damage) osteoarthritis [21]. Similarly, recent suggestions propose that generalised chronic pain is an expression of maladaptive plasticity within the nociceptive system [22, 23] and is relevant to the present chapter as osteoarthritic pain is generally accepted to be mainly of nociceptive origin [24].
\nMost painful conditions initially involve the activation of dorsal root ganglion (DRG) neurons, which give rise to high threshold Aδ- and C-fibres (nociceptors) that innervate peripheral tissues (skin, bone, joints, viscera; [25]). Primary afferent neurons transduce painful stimuli action potentials through to the spinal cord (to ascending spinal neurons). Transmission of input from nociceptors, through the spinal column and to the central nerves system is mediated by monosynaptic contacts and/or through interneurons [19, 26]. In the spinal cord, neurotransmitter inhibition is mediated by the release of endogenous opioids (such as met-enkephalins and endorphins; [27]) or gamma-aminobutyric acid (GABA) which activate presynaptic opioid and/or GABA receptors on central nociceptor terminals to reduce excitatory transmitter release (Figure 1). The central integration of signals from excitatory and inhibitory neurotransmitters from cognitive, emotional, and environmental factors results in the perception of “pain”. When the intricate balance between biological (neuronal), psychological (i.e. memory, distraction etc.) and social (i.e. attention, reward etc.) factors becomes disturbed, chronic pain develops [18].
\nPeripheral and central nociceptor pain signalling pathways following exposure to different pharmaceutical drugs. Without pharmaceutical intervention (naive state), activation of peripheral nociceptors in response to noxious stimuli, such as mechanical stress (OA) initiates the release of chemical mediators such as prostaglandins, bradykinin and cytokines at the peripheral terminal of the afferent neuron (peripheral sensitisation) which is modulated by the GPCRs, NA+ and K+ channels. This results in the activation of PKA, PLC releasing intracellular Ca2+ and the generation of action potential which transfers information to the (pre synapse) C-terminal afferent neuron (central sensitization). This triggers the release of neurotransmitters i.e. glutamate and substance P into the spinal synapse of the dorsal horn and activates AMPA or NMDA receptors on the post synaptic dorsal horn. As a result, there is an increased influx of Ca2+ and Na+, inhibition of K+ influx and depolarization of the cell membrane. These signals travel to the brain where they are transcribed into the perception of pain. Pharmaceutical invention acts by modulating various aspects of the pain signalling pathway such as opioids (opioids such as morphine bind to GPCRs preventing the presynaptic release of a number of neurotransmitters), NSAIDs (inhibit the activity of COX) and acetaminophen (inhibits the activity of COX in the central nervous system but appears to lacks peripheral anti-inflammatory properties). Figure created using
Pain that is induced by an acute injury, initially localised, relatively proportional to the degree of tissue damage and typically increases with movement is referred to as “nociceptive pain.” Specifically, as immune surveillance cells recognise the danger signals unmasked by tissue injury, the innate immune system initiates an inflammatory response to remove cellular debris and begins the healing process. Activated endothelial cells, stromal cells, and infiltrating immune cells release vasoactive and inflammatory mediators, including histamine, bradykinin, substance P, serotonin, nitric oxide, cytokines, chemokines, and prostaglandins, which amplify signal transduction in the peripheral terminals of nociceptors [26, 28]. These inflammatory mediators augment the responsiveness of nociceptors by increasing expression of pain-sensing ion channels and promoting release of pronociceptive mediators (autosensitization; [29]). This peripheral inflammation caused by local injury and continuous inputs from sensitised nociceptors promote ‘central sensitization’, a process that alters pain processing in the spinal dorsal horn, and in subcortical and cortical regions of the brain [30, 31]. Noxious signals associated with the injury are detected by peripheral nociceptor terminals of primary afferent neurons, transmitted via the spinal cord to the brain, processed and interpreted as highly unpleasant pain experiences [32]. Nociceptor terminals express molecules, such as transient receptor potential ion channels (TRP), voltage-gated sodium channels (Nav), voltage-gated calcium channels (VGCC), or acid-sensing ion channels (ASICs), which respond to heat, cold, acids, or mechanical stress and transduce them into action potentials [26]. The signal is then transmitted through peripheral axons to the cell bodies of the primary neurons, located in the dorsal root ganglia. Unmyelinated C-fibres and myelinated Aδ-fibres transmit noxious stimuli, whereas thinly myelinated Aδ-fibres transmit innocuous mechanical stimuli, such as touch. The central axons of the primary neurons enter the spinal cord through the dorsal horn and synapse with secondary somatosensory neurons and, to some extent, with motor neurons to form withdrawal reflex circuits. Signal propagation to the secondary neurons is subject to modulation by descending tracts from the brainstem and by interneurons in the dorsal horn. The signal is then transmitted to the thalamus, from where tertiary afferent neurons are projected to multiple areas of the cortex involved in pain processing [33].
\nNeuropathic pain (NP) is defined as “pain caused by a lesion or disease of the somatosensory nervous system” [34]. Chronic neuropathic pain is caused by damage to nerve fibres that respond by misappropriating sensory inputs leading to spontaneous painful sensation, through multiple mechanisms in the nervous system and its associated modulators. Peripheral nerve damage can result in chronic neuropathic pain through multiple routes [35] via peripheral pain-processing unmyelinated C-fibres and thinly-myelinated fibres because of metabolic damage, toxins, medications, cytokines, and inflammation [36]. This can result in morphological and chemical changes such as fibre density and neuronal hyperexcitability [30, 37, 38, 39, 40]. Throughout the axon, trauma, compression, hypoxia, inflammation and chemical damage lead to fibre degeneration and alterations in gene expression [41], resulting in ectopic firing, faulty signal transmission [42], detrimental physiological alterations [43, 44, 45] and peripheral second-order targets [46, 47, 48]. This results in negative impacts on nociceptive pathways causing them to become sensitised [49], leading to maladaptive central sensitization [50] and increased responsiveness of nociceptive neurons in the central nervous system to their normal or subthreshold afferent input [51]. At the molecular level, these damaged processes disrupt second-order neuronal transduction, through alterations in receptor expression, calcium permeability, synapse location and the release of pain-promoting mediators [52, 53, 54, 55]. The precise molecular targets of neuropathic pain stem from multiple mechanisms of peripheral nerve fibre excitation and sensitization leading to sustained electrochemical signalling and to neuropathic pain stimulus [56, 57].
\nBoth acute and chronic pain are, in general, treated with a wide group of pharmaceutical medications known as “analgesics.” The most frequently used are opioids, nonsteroidal anti-inflammatory drugs (NSAIDs) and paracetamol, also referred to as acetaminophen or N-acetyl-p-aminophenol [58].
\nOpioid drugs (e.g. morphine, codeine, methadone, fentanyl and their derivatives) are the most widely used analgesic medications globally, so much so that an estimated 26.8 million people were living with ‘opioid use disorder’ globally in 2016, resulting in >100,000 opioid overdose deaths annually [59]. Opioids are a group of pharmaceutical formulations that interact with endogenous opioid receptors to distort neurotransmitter singling pathways through localised peripheral sensory neurons [60, 61] with the goal to reducing pain sensation. Opioid receptors are a large superfamily of seven-transmembrane G protein-coupled receptors and are classified as μ (μ1, μ2, μ3), δ (δ1, δ2), k (k1, k2, k3) and ORL1 [62, 63], of which almost all opioid drugs in use today interact with μ receptors. These receptors are inhibitory and prevent the presynaptic release of a number of neurotransmitters to inhibit the release of glutamate, calcitonin gene related protein (CGRP), and substance P. This is an important action considering the established roles of these molecules in pain signalling and nociceptive transmission (Figure 1; [64]). For example, morphine, extracted from opium, is by far the most commonly known opioid [59], which is thought to have been in use since the third century B.C. [22], but identified at the molecular level with high binding affinity to sites in the intestine and brain [65]. These receptors mediate an inhibitory signal of neural transmission induced by opioid drugs to produce an analgesic action (Figure 1). Pain stimuli are detected by nociceptors at the spinal cord dorsal horn [66] where they act on the substantia gelatinosa (inhibitory interneurons rich with opioid receptors) and are activated by the antinociceptive descending system, to control the transmission of painful stimuli from primary nerve fibres to spino-thalamic neurons [22]. Opioid receptors have an intricate relationship with inflammatory status. Early studies showed that the systemic or local application of receptor agonists elicited greater analgesic effects in inflamed compared to non-inflamed tissue (reviewed in; [67]). Furthermore, opioid receptor trafficking (movement within the neuron) is augmented, expression on DRG membranes is enhanced [68, 69] and axonal transport stimulated by cytokines and nerve growth factor that are produced within inflamed tissues [70, 71]. This enhanced/altered state resulted in increased antinociceptive function of opioid receptors on peripheral nerves [60, 72].
\nThe major limiting factors of opioid therapy are the variety of side effects such as constipation, vomiting, myosis, cough reflex suppression, modulation of the immune system and one of the most dangerous, respiratory rhythm and respiratory depression [73, 74]. Interestingly, studies have shown that long-term use in chronic non-malignant (e.g. musculoskeletal) pain has not been proven effective [75], rather, abuse of prescription opioids have reached epidemic proportions leading to addiction, overdoses and increased death rates [76, 77, 78]. Importantly, these side effects may be drug specific and affect immune function differently [79, 80]. Nonetheless, chronic use of opioid medication can cause cellular adaptions that lead to modulation of cellular growth, inflammation, wound healing [81, 82]. For a more detailed overview of the potential side effects and opioid tolerance refer to the following references [83, 84, 85, 86].
\nRegardless of the potential impact that opioid agonists could have on pain relief, meta-analyses show no improvement in clinically significant pain reduction scores, and epidemiological data suggest that quality of life and functional capacity are only minimally changed [75, 78]. Nonetheless, more data is required from larger studies (specifically in OA), however the aforementioned adverse effects and lack of analgesic efficacy has led to significant dropout rates in long-term studies [75, 78, 87, 88, 89].
\nNSAIDs (particular enzyme inhibiters) are among the most widely used medications globally [90, 91] because of the lower potential for addiction (as shown by the US opioid epidemic; [92]), robust efficacy, and long history of clinical use [93].
\nThe prevalence of ‘non-aspirin’ NSAID use has been well studied and is dynamic across age, body mass index and geographical ancestry, ranging between ~15-45%, women being the highest users and ibuprofen generally being the most reported [94, 95, 96]. Short-term use of NSAIDs is particularly prevalent (~50–80% per year) in athletes and soldiers (individuals that may be at risk for acute and chronic musculoskeletal injuries; [97, 98, 99]). Extended periods of NSAID treatment (e.g., more than 3 times per week for more than 3 months per year) have been reported in 10% of adults in the United States [100], a rate that can be expected to increase with age [101].
\nNSAIDs act primarily by mediating peripheral pain sensitization driven by inflammatory stimuli, such as acute or sport injuries, (osteo)arthritis etc. and are less effective in treating pain due to nerve damage (neuropathic pain). At the point of inflammatory pain, initiated by nociceptive stimuli, NSAIDs augment the experienced nociceptive excitability (peripheral and central sensitization; [102]). NSAIDs work differently to opioids in that they do not block central pathways of nociception, but inhibit the formation of prostanoids via competitive inhibition of arachidonic acid binding to cyclooxygenase enzyme (COX) isoform active sites [103], which sensitise nociceptive pain. There are two cyclooxygenase isoforms that are the targets of NSAIDs; COX-1 that are expressed in most tissues (including the endothelium, monocytes, gastrointestinal epithelial cells, and platelets) and controls the basal production of prostanoids (Figure 1) and COX-2 that are not regularly expressed in most tissues but are upregulated in response to and during the inflammatory process (in tissues such as vascular endothelium, rheumatoid synovial, endothelial cells, monocytes, and macrophages) through the actions of various inflammatory mediators such as bacterial endotoxins, tumour necrosis factor-alpha and interleukins [104]. The increase in COX-2 protein levels are the primary driving force for enhanced production of prostanoids at inflammatory sites [105, 106]. The resulting COX-2 products, particularly prostaglandin (PG) E2, potentiate this response, where PGE2 and prostacyclin (PGI2), produced during local inflammation, augment pain signalling by peripheral and central neurons [15]. PGE2 and PGI2 increase the sensitivity of pain receptors (or nociceptors) in the periphery and enhance the activity of various pain mediators [104, 107]. This mechanism propagates via brain derived PGE2 travelling through the blood–brain barrier, via venules, during systemic inflammation and lessens the inhibition of neurons in the hypothalamus [108]. Drugs that inhibit both COX isoforms with comparable potency (i.e. nonselective NSAIDs such as ibuprofen and ketoprofen) tend to preferentially activate the COX-1 pathway, while drugs with intermediate or selective target COX-2 inhibition (such as nimesulide, meloxicam, diclofenac, celecoxib, rofecoxib, etoricoxib, lumiracoxib etc.) have lesser potential for COX-1 activation [109]. This pathway selectivity is of significant importance as both COX isoform elicit different potentially harmful adverse effects.
\nIn a recent meta-analysis (n = 220,000 patients) of placebo-controlled trials, NSAIDs (coxibs, diclofenac, ibuprofen, and naproxen, predominantly COX-1 inhibiters) significantly increased the risk of upper gastrointestinal complications [eg, ulcer perforations, bleeding, obstructions; 110]. The authors also showed an increased risk of major vascular and coronary events with high doses of coxibs and diclofenac while ibuprofen was associated with an increase in major coronary (but not vascular) events comparable with that of coxibs and oral diclofenac (predominantly COX-2 inhibiters; [110]). These data are corroborated with findings from meta-analysis of observational studies showing low risk of upper gastrointestinal complications (aceclofenac, celecoxib, and ibuprofen predominantly COX-2 inhibiters), intermediate risk (diclofenac, meloxicam, and ketoprofen etc.) and high risk (tenoxicam, naproxen, indomethacin, diflunisal, piroxicam, ketorolac, and azapropazone predominantly COX - inhibiters) depending on the NSAID, likely in a dose dependent fashion [111]. Similarly, total daily oral diclofenac had a linear dose dependent relationship cardiovascular event risk [112]. These dose dependencies are likely a product of the relative effectiveness on either COX-1 or COX-2 inhibition [113, 114, 115, 116]. As both (non-inhabited) COX-1 and COX-2 produce cytoprotective prostanoids, inhibition of both COX isozymes (induced by NSAIDs) suppress these prostanoids and promotes damage to the gastrointestinal tract and cardiovascular tissues [109, 117]. Based on these and other safety findings, the American Heart Association recommends patients take the lowest effective dose of NSAIDs for the shortest duration of time [118].
\nAPAP are likely to be the most commonly used pharmaceutical worldwide [119, 120], are expected to reach a global market value of USD 999.4 million in 2020 [121] and is included in the 21st World Health Organisation Model List of Essential Medicines as updated in March 2017 [122]. However, recently there have been debates from the National Institute for Health and Care Excellence, about the relevance of APAP for some conditions [123]. The efficacy of paracetamol to treat chronic pain has been questioned with systematic reviews showing limited (sometimes null) effects on chronic pain in some conditions [120, 124, 125]. Nonetheless, APAP can be beneficial for acute pain, [126, 127, 128], similar to NSAIDs and opioids [129, 130, 131]. The precise mechanism of action remains unknown, however this is most likely due to the interwoven interactions that APAP have in multiple pain pathways. Our current knowledge suggests that APAPs are metabolised by the liver into p-aminophenol, then bound with arachidonic acid, primarily in the brain, to form AM404 (N- (4-hydroxyphenyl)-5Z,8Z,11Z,14Z-eicosatetraenamide) through fatty acid amide hydrolase (FAAH) activity [132, 133, 134]. Like NSAIDs, APAP are analgesic and antipyretic, however APAP lacks peripheral anti-inflammatory properties, therefore act through the central nervous system and not peripheral tissues [135]. Current evidence suggests that there are four metabolic systems that interact to elicit the analgesic and antipyretic properties of APAP, the Eicosanoid, Opioidergic, Seretogentic and Endocannabinoid systems [136].
\nBriefly, like NSIADs, APAP can inhibit central cyclo-oxygenases (COX-1, COX-2) including a proposed third isoform COX-3 [137, 138, 139, 140, 141, 142]. Although the results are controversial [143] it is thought that they are involved in prostaglandin (PGs) production thus the analgesic mechanism of action. Furthermore, APAP are more effective in environments with low peroxide tone and low arachidonic acid levels, such as in the central nerves system, mainly through local depletion of glutathione leading to decreased production of PGE2 [139]. Considering the antinociceptive effects of APAP, one of the main brain derived metabolites AM404 (N-arachidonoyl-phenolamine) is decrease in the presence of opioid receptor antagonist. AM404 inhibits the nociceptive activity of particular APAPs in part by modulating many neurotransmitters, including 5-HT, glutamate, and γ-aminobutyric acid [143, 144, 145]. Although the precise receptors have not been identified [146, 147, 148, 149], serotonin antagonists block the analgesic effect of APAP through mainly indirect non-binding mechanisms [146, 150]. One possible interaction with the serotonergic pathway maybe though altering CNS monoamine neuron types in the brain that contain a major receptor for PGE2 (EP3 receptor [139]). Further to the above, AM404 can inhibit anandamide [151], with stimulation of (canobinoide 1) CB1 receptor activity (without binding) via FAAH [133], suggesting a reliance of APAP antinociceptive activity on interaction with the endocannabinoid system [134, 152]. Interestingly, AM404 is not identifiable in the blood after APAP administration [133] which might explain, to some degree, the absence of peripheral anti-inflammatory action [134]. This could help to explain why APAP may not have significant clinical effect on conditions such as osteoarthritis (further details below; [153, 154]). A recent study confirmed that APAPs act mainly on central analgesic pathways, showing that APAP modifies the activity and connectivity of analgesia via FAAH, activating a signalling cascade involving TRPV1 channels, mGlu5 receptors, PLC, DAGL and CB1 receptors, associated with the release of glutamate and GABA – through the endocannabinoid systems [155]. Though the molecular mechanisms that provide analgesia are beginning to come to light, there is also potential substantial detrimental side effects of APAPs.
\nAPAPs are generally considered safe if administered at appropriate doses for short periods [156]. However, they remain one of the leading causes of liver disease in high-income countries [157, 158] which has led to legislative restrictions in many countries [159]. It is well accepted that APAPs cause liver injury, hepatotoxicity, mitochondrial toxicity [160, 161] and that this toxicity can be effected by interindividual variation [162]. Nonetheless, consuming APAP can increase the risks of hospitalisation for perforation, peptic ulceration and bleeding [163], relative rates of adverse cardiovascular events such as myocardial infarction, stroke, coronary heart disease and upper gastrointestinal disease such as gastroduodenal ulcers and haemorrhages [164], often in a dose response manor. However, observational studies show a favourable side effect profile for APAPs compared with NSAIDs when used in older people with chronic pain conditions [165]. Data from the most recent meta-analysis shows that APAPs are nearly four times more likely to have abnormal results on liver function tests than placebo [166].
\nOsteoarthritis (OA) is a complex musculoskeletal condition that effects people of all ages but particularly those over 55 years [167, 168, 169, 170, 171]. According to the Osteoarthritis Research Society International (OARSI) OA can be defined as;
\nOA is a pro-inflammatory branch of rheumatic disease that effects synovial joints progressively and is caused by the failure of joint tissues to repair following damage. This damage may have been caused by stresses due to an abnormality in the articular cartilage, subchondral bone, ligaments, menisci, periarticular muscles, peripheral nerves or synovium [173, 174]. While cartilage degradation is the traditionally structural trademark of OA, it is generally considered a whole joint disease with many other morphological features [175, 176, 177, 178]. For example, an osteoarthritic joint may exhibit sclerosis in the subchondral bone, osteophytes [179], local inflammation such as synovitis [177, 178, 180, 181] and bone marrow lesions [182]. Failure of normal biological repair processes that leads to breakdown of cartilage and bone [183] is characterised by symptoms of pain, stiffness, functional disability [184] that can lead to negative impacts on fatigue, mood, sleep, overall quality of life [185, 186].
\nOA confers a number of modifiable and non-modifiable risk factors [174, 187]. Non-modifiable risk factors include previous joint injury [188, 189], malalignment and other mechanical factors [175, 176, 190, 191, 192, 193], age [189], sex [194], ethnicity [195] and genetic predisposition [196, 197, 198]. Modifiable risk factors include obesity [181, 189, 199, 200, 201, 202], metabolic syndrome [181, 203, 204, 205, 206], in particular diabetes mellitus [207, 208, 209] and habitual diet [187, 210].
\nThe condition is one of the most common causes of chronic pain and the most common cause of joint pain [211] with conservative estimates suggesting that there are approximately 500 million suffers worldwide [167, 212]. OA affects ~13% of all over 50’s (~7% in all ages; [213]) and has no cure [214, 215, 216, 217, 218] while being the 11th highest contributor to years lived with disability [159].
\nChronic inflammatory-associated pain can have multiple mechanisms [219, 220, 221, 222, 223] and can stem from mechanical stress or central sensitization either concurrently and/or vary in their influences over time [224]. Pain derived from OA can generally be characterised into two common clinical forms of pain, intermittent but severe/intense and persistent pain or aching [225]. These pain experiences can come from neuropathic and nociceptive process, as discussed above. The prevalence of neuropathic pain features at the knee in OA patients ranges from 19% to 29% [221, 226, 227]. However, recent studies of peripheral and central nerve sensitization [228], as well as nerve ending damage and regrowth [229, 230] have shown that neuropathic pain contributes substantially to the condition. This central sensitization is prominent in those that experience a high level of pain that is not proportional to radiographic evidence of structural damage [219] and contributes more to the pain experienced in women with symptomatic OA, compared to men [231]. Generally, a higher degree of central sensitization or neuropathic pain is associated with high pain intensity and a greater chance of developing chronic pain following joint replacement [232, 233]. The remaining 70-80% of knee OA pain appears to be nociceptive in nature, thus OA can be described as a chronic mild to moderate nociceptive dominant pain condition [24, 234] and should be considered as such with regards to initial treatment [24].
\nThe diversity of pathophysiological maladaptation in OA effected joints and the low associations of these changes with pain, suggests doubt over the link between joint structural condition and the experience of pain. This is evident from the poor relationship between radiographic images and reported pain. A recent systematic review showed that the prevalence of knee pain in patients with radiographic knee OA ranged from 15% to 81% [235]. However, some studies reported associations between the structural damage of the joint (cartilage and bone) and pain [236] but at higher levels of X-ray derived pathology (Kellgren/Lawrence grade; [237]). Nonetheless, pain may still indicate a level of disease activity. In a number of studies looking more specifically at joint morphological characterises, OA pain has been associated with the rate of medial cartilage loss (also after adjustment for radiographic OA stage; [238]), osteophytes [239], more erosive OA compared to non-erosive OA [240] and changes of bone marrow lesions and synovitis [182]. These data show the complexity of the disease-pain nexus and suggests that the disease should, in the first instance (i.e. mild OA), be treated generally with lifestyle and nutritional intervention rather that pharmaceuticals that target specific pathological pathways (Figure 1) [241]. Regardless, pharmaceutical therapies remain the main treatment for such conditions [242].
\nOA is a progressive condition with no cure where opioids, acetaminophen and non-steroidal anti-inflammatory drugs (NSAID) are the traditional, non-lifestyle, approach for early management. However, as eluded to earlier, these pharmaceutical treatments are often accompanied with significant side effects. For example, NSAIDs are the traditional approach for early clinical management of mild-to-moderate OA [241] and in the US 65% of all OA patients are prescribed NSAID for pain management - this is the current recommended strategy for OA clinical management by the leading authorities [243]. While some NSAIDs are effective at improving pain and physical function, they come with significant and potentially harmful side effects such as gastrointestinal complications, renal disturbances and severe cardiovascular events [244]. Although some of these risks may be reduced using topical administration such as Diclofenac gel/cream [245, 246]. Two recent large-scale studies have shown that, depending on the particular medication, the risk of hospital admissions (due to heart failure) can be nearly two times greater (Ketorolac; [247]) in OA/rheumatoid arthritis (n = 24,081), with ibuprofen (generally speaking, the most used NSAID) presenting with the highest rates of NSAID toxicity [248].
\nApproximately 34% of OA patients use Paracetamol [249], in isolation or in combination with NSAIDs. In fact, the effectiveness of Paracetamol to improve pain management has recently been called into question [124], as it has been shown to be ineffective for treating OA pain [125, 250] and may have similar side effects as ibuprofen [251], particularly when consumed at higher doses [164]. Specifically, in knee or hip OA, a recent Cochrane review concluded that Paracetamol provides no clinically important improvements in pain in the immediate and short term (up to 12 weeks; [16]). In addition, a recent network meta-analysis (56 randomised controlled trials, 22 128 participants) suggests that paracetamol was least effective for the treatment of knee and/or hip OA compared with celecoxib (NSAID) or the combination of glucosamine and chondroitin [117] – confirming other reports [252]. In contrast, some authors have concluded that paracetamol had similar efficacy to NSAIDs for the treatment of OA [253]. It is also important to remember that overuse of APAPs can cause liver injury, hepatotoxicity, mitochondrial toxicity [160, 161] which is relevant to a chronic condition with no known cure. These data led to confusion in earlier guidelines that consistently recommended the prescription of paracetamol (acetaminophen) as the first line analgesic for these conditions [90, 91, 241, 254, 255]. However, the data are now relatively clear that there is little clinically meaningful effect of Paracetamol for OA pain [153, 154].
\nThe potential negative effects such as addiction and the physiological side effects of opioid use are well documented, as discussed above, however they remain highly prescribed for OA and are expected to triple in the coming years [256, 257]. More than half of those prescribed opioids in the first year of OA have been shown to be inappropriately dispensed [257]. The prevalence of opioid use for OA ranges from 8-26% and in Australia, with the use for knee/hip OA has being described as “alarmingly high” [257]. A number of systematic reviews and meta-analysis have been performed in recent years and have unanimously shown that the tolerability is low, efficacy for pain relief in OA is not clinically relevant and the potential harms are high [258, 259, 260]. Despite calls for guidelines to be changed on the use of opioids and the above-mentioned pharmaceuticals, their use is increasing (likely with the prevalence of the disease) and by proxy the negative consequences rising in tandem. Therefore, non-pharmaceutical food-based alternatives (termed bioactive nutraceuticals) have been developed and are beginning to be recommended as early treatment [261, 262, 263] to improve OA symptoms including pain [241, 264, 265, 266].
\nGiven the possible side-effects of pharmaceutical treatments, any reduction in their use is of particular importance to OA public health. As such, a number of non-pharmaceutical alternatives have been developed that may reduce the use/required dose of pharmaceuticals while maintaining or improving the impacts on OA pain and physical function. The majority of these alternatives are termed “nutraceuticals” (a portmanteau of the words “nutrition” and “pharmaceutical”), coined in 1989 by Dr. Stephen DeFelice [267], founder and chairman of the Foundation for Innovation in Medicine.
\nWhile it is unlikely that Hippocrates (traditionally regarded as the father of modern medicine; died 375 BCE) actually said: “Let food be your medicine and medicine your food” [268], this is often cited in the context of nutraceuticals. A more apt and legitimate quote defines the position of nutraceuticals in health and disease as “beyond diet, before drug”, coined by Ettore Novellino in 2012 [269].
\nThere is currently no universally accepted definition of a nutraceutical [270], with the main confusion being the differences between nutraceuticals and functional foods, and the lack of regulatory definition between them (Table 1) [270, 271, 272, 273]. In fact, current European regulations do not distinguish between nutraceuticals and food supplements (see the EC Regulation n. 1924/2006 of the European Parliament and Council, recently updated by the UE regulation 2015/2283), therefore neither does the European Food Safety Authority [274, 275]. However, a number of proposed definitions exist (Table 1) and from these definitions, for the purposes of this chapter, a nutraceutical will be defined as;
\nAuthor(s) | \nDefinition | \n
---|---|
DeFelice, [267]; coined in 1989 | \n“A nutraceutical is any substance that is a food or part of a food and provides medical or health benefits, including the prevention and treatment of disease.” | \n
Zeisel, [271] | \n“……as those diet supplements that deliver a concentrated form of a presumed bioactive agent from a food, presented in a non-food matric, and used to enhance health in dosages that exceed those that could be obtained from normal food” | \n
U.S. Nutraceutical Research and Education [276] | \n“a dietary supplement, food or medical food that has a benefit, which prevents or reduces the risk of a disease or health condition, including the management of a disease or health condition or the improvement of health; and is safe for human consumption in the quantity, and with the frequency required to realise such properties” | \n
The European Nutraceutical Association [277] | \n“are nutritional products that provide health and medical benefits, including the prevention and treatment of disease. In contrast to pharmaceuticals however, these are not synthetic substances or chemical compounds formulated for specific indications. These are products that contain nutrients (partly in concentrated form) and mostly are assigned to the category of food. Dietary supplements are a typical example for nutraceuticals, but also dietetic and functional foods may be counted among these products.” | \n
Health Canada [278] | \n“A nutraceutical is a product isolated or purified from foods that is generally sold in medicinal forms not usually associated with food. A nutraceutical is demonstrated to have a physiological benefit or provide protection against chronic disease” | \n
Corzo et al. [279] | \n“Nutraceuticals are biological substances extracted from natural sources by non-denaturing processes to preserve their original properties without any chemical manipulation.” | \n
Currently used definitions to describe nutraceuticals.
As such, the following sections will discuss those nutraceuticals that are currently not in mainstream use but may have the potential to aid in treatment of OA (i.e. the well discussed Glucosamine and Chondroitin will not feature in this chapter) but are in regular use worldwide [280]. The identified nutraceuticals that have been compared to/with NSAID/analgesics for OA can be divided into three categories, defined by their origin, and are presented in Table 2;
Terrestrial Botanicals, compounds derived from ‘land’ plant sources (avocado/soybean, pine bark extract and turmeric/curcumin).
Marine Botanicals, compounds derived from ‘marine’ plant sources (Lithothamnion species).
Marine Fauna, derived from marine animals (fish oil and green lipped mussel).
Proposed main active compound | \nTreatment regime | \nEffect on OA Analgesia and NSAID | \nReference | \n
---|---|---|---|
Avocado/soybean unsaponifiables | \nAvocado/soybean unsaponifiables 300 mg or 600 mg ASU for 3 months | \n↓ NSAIDs and analgesics use by 50% vs. placebo ↓ pain (~50%) in both 300 mg and 600 mg vs. placebo | \n[281] | \n
Avocado/soybean unsaponifiables | \nPiascledine/ASU (300 mg daily) for 6 months | \n↓ Participants using analgesics and NSAIDs (from 58.8% to 24.9%) ↓ Median pain (by ~50%) and pain intensity, pain at rest (by 100%) and pain during walking (by ~60%) ↓ Mobility score (by ~50%) | \n[282] | \n
Avocado/soybean unsaponifiables | \nAvocado/soybean mixture, 300 mg daily orally versus celecoxib,200 mg/day orally for 8 weeks | \n↓ Cartilage oligomeric matrix protein (COMP) in both groups (by ~37%, Avocado/soybean and ~ 27%, celecoxib), with no differences between groups | \n[283] | \n
Fish oil/ | \nPhytalgic (fish-oil, vitamin E, Urtica dioica) 3 capsules daily for 12 weeks | \n↓ NSAIDs use vs. the placebo (by ~60%) ↓ Analgesic use vs. the placebo (BY ~40%) ↓ Pain (by ~37%), stiffness (by ~43%) and function (by ~40$) vs. placebo | \n[284] | \n
Green lipped mussel | \n600 mg of BioLex(R)-GLM extract daily or placebo for 12 weeks | \n↓ Paracetamol use (by ~30% post-trial) vs. placebo ↓ Stiffness (by ~19%) vs. placebo, no difference pain | \n[285] | \n
Pine bark extract | \nPycnogenol (pine bark extract) 100 mg for 3 months | \n↓ Use of drugs (by ~57%) vs. placebo ↓ Gastrointestinal complications (by ~60%) vs. placebo ↓ WOMAC score (by ~40%) vs. placebo ↑ Walking distance (by ~34%), compared to no improvement in placebo | \n[286] | \n
Turmeric | \nTurmeric extracts (2 g extracts/day) or ibuprofen (800 mg) for 0, 2, 4 and 6 weeks | \n↓ Pain on walking stairs vs. ibuprofen (however, ibuprofen was greater at baseline thus throughout) No difference in pain on level walking, 100 m walking time or stair climb | \n[287] | \n
Turmeric | \nTurmeric extracts (1500 mg extracts/day) or ibuprofen (1200 mg/day) for 4 weeks | \n↓ WOMAC score, pain and function compared to baseline scores at all time points, and was non-inferior to ibuprofen. ↓ Rate of abdominal pain/distention vs. ibuprofen (by ~60%) | \n[288] | \n
Curcumin | \nBCM-95® Curcumin: 500 mg/capsule twice daily, Curcumin 500 mg + diclofenac sodium 50 mg/capsule twice daily, diclofenac 50 mg/ capsule twice daily, all for 8 weeks | \n↓ Disease Activity Score (by ~45%), CRP (by ~52%), American College of Rheumatology score, improved pain (by ~60%), erythrocyte sedimentation rate (by ~11%), greater in Curcumin and Curcumin+ diclofenac vs. diclofenac alone | \n[289] | \n
Curcumin | \nBCM-95® (curcumin, demethoxycurcumin, bisdemethoxycurcumin, and volatile oils from turmeric rhizome), 500-mg three times daily versus diclofenac 50-mg tablet two times daily for 28 days | \n↓ Pain similar in both groups (by ~78% for both), no difference between groups ↑ KOOS variables (n = 5) similar in both groups, no difference between groups ↑ Flatulence in diclofenac vs. curcumin (by ~79%) ↓ Requirement for H2 blockers in curcumin vs. diclofenac (by 100%, i.e. zero in curcumin) ↓ Incidence of adverse effects in curcumin vs. diclofenac (by ~76%) | \n[290] | \n
Curcumin | \nLongvida®, 800 mg patented lipophilic matrix delivering 160 mg curcumin versus Ibuprofen (400 mg) orally and daily for 12 weeks | \n↓ Pain in both (by ~60%), no difference between groups | \n[291] | \n
Curcumin | \nHerbal formulation of curcumin (300 mg), gingerols (7.5 mg), and piperine (3.75 mg; Mixodin) versus Naproxen 250 mg capsules, both twice a day for 4 weeks | \n↓ prostaglandin E2 (PGE2) in booth groups with no difference between the two (~27 pg./mL) | \n[292] | \n
Curcumin | \nMeriva tablets, a curcumin-phosphatidylcholine phytosome complex, 200 mg equivalent curcumin daily with best available care (BCA) compared to BCA only as control for 8 months | \n↓ NSAIDs use (by ~80%) vs. control ↓ Gastrointestinal complaints (by ~40%) vs. control ↓ Pain (by ~44%), stiffness (by ~28%), physical function (by ~40%), WOMAC score (by ~41%), compared to no improvements in controls ↑ Karnofsky Performance Scale (by ~22%), compared to no improvement in controls ↑ Treadmill walking distance (345% increase from baseline) compared to 89% in controls ↓ inflammatory markers sCD40L (by ~56%), IL-1β (by ~35%), IL-6(by ~27%), sVCAM-1 (by ~30%), ESR (by ~25%), compared to no change in controls | \n[293] | \n
Curcumin | \nTheracurmin® (10% of curcumin, 2% other curcuminoids such as demethoxycurcumin and isdemethoxycurcumin, 46% glycerin, 4% gum ghatti, and 38% of water; 180 mg of curcumin) for 8 weeks | \n↓ NSAID (celecoxib) dependence (p = 0.0252) ↓ Pain (by ~55%) vs. placebo | \n[294] | \n
Curcumin | \nC3 complex, 500 mg curcuminoid capsules including 5 mg Bioperine, 3 times daily for 6 weeks | \n↓ Naproxen use (by ~73%) vs. controls ↓ Pain (by >38%), function (by ~41%) and WOMAC score (by ~41%) vs. placebo | \n[295] | \n
Ginger | \nTopical ginger extract gel (4% gel Plygersic) versus sodium diclofenac gel applied 1 mL of solution 4 times a day for 6 weeks | \n↓ Pain (by ~27%), symptoms (by ~27%) No difference in the above between groups | \n[296] | \n
Ginger | \nDiclofenac 50 mg orally or Ginger 750 or Ginger 750 mg and Diclofenac 50 mg orally for 12 weeks | \n↓ Pain and WOMAC score in all three groups, greatest improvement with Ginger (60%; 75%) the addition of ginger to Diclofenac (67%; 79%), compared to Diclofenac alone (59%; 64%) ↓ Use of rescue medication (paracetamol) in Ginger (50%) and Ginger with Diclofenac (87%) compared to Diclofenac alone (not statistically significant) | \n[297] | \n
Lithothamnion species (Red Algae) | \nAquaminF, 267 mg Lithothamnion, 3 capsules per day, 3 times a day for 12 weeks | \n↑ ROM (by 5.2°) and 6MWD (By 136 ft) following 50% forced reduction from all NSAID in AquaminF vs. placebo No difference in rescue medication (acetaminophen) consumption between groups ↑ Six meter walking distance (by~92%) following 50% forced reduction from all NSAID in AquaminF vs. placebo | \n[298] | \n
Lithothamnion species combination | \nAquamin+, 2668 mg Lithothamnion, 268 mg seawater-derived Mg(OH)2 and pine bark extract 120 mg versus 2000 mg Glucosamine Sulphate Daily dose for 12 weeks | \n↓ Pain (by ~11%), symptoms (by ~7%), no change in Glucosamine ↑ Sport and recreation (by ~9%), no change in Glucosamine ↑ Timed up and go performance (by 7%), no change in Glucosamine ↓ Rescue analgesic use (by 72%) vs. Glucosamine | \n[299] | \n
Nutraceuticals shown to reduce analgesic and NSAID use.
Turmeric/curcumin extracts (spices used mainly in South Asian cooking) or nutraceuticals combinations where turmeric/curcumin extracts are the main active ingredient, have the greatest amount of evidence for improving OA symptoms, with some recent data on NSAID and analgesics use (Table 2) [300]. Two studies have directly compared raw turmeric/curcumin extracts to NSAIDs and their effectiveness for OA symptoms [287, 288]. These data show that turmeric extracts either improved or were shown to be non-inferior for knee osteoarthritis (KOA) pain, pain during stair walking and resulted in less side effects (particularly the rate of abdominal pain/distention) compared to oral ibuprofen [287, 288, 289]. Furthermore, patented/propriety formulations of turmeric/curcumin extracts have been developed around the world and show some promising effects on OA (Table 2). Interestingly, Chandran et al. demonstrated that curcumin formulated as BCM-95® or ‘BCM-95® + diclofenac sodium’ showed superior ‘Disease Activity Scores’, American College of Rheumatology score, pain, CRP levels and erythrocyte sedimentation rate, compared to diclofenac alone (Indian population; [289]). The same formulation showed similar improvements of KOOS variables, but BCM-95® resulted in less adverse events (including flatulence) and a lower requirements for H2 blockers (0% vs. 28%; a group of medicines that reduce the amount of acid produced by the cells in the lining of the stomach), compared to diclofenac [290]. In the longest of these studies (8 months in a European cohort), the addition of Meriva® (curcuminoids 20%, phosphatidylcholine 40%, and microcrystalline cellulose 40%) to the “best available treatment”, reduced NSAID and analgesia use by 63% compared to the control group (“best available treatment” only). This reduction resulted in less side-effects between 45-67%, depending on the specific adverse advent, compared to side-effects in the control group (2-12%; [293]). Similarly, an alternative preparation (C3 complex®; Curcuminoids 500-mg capsules with 5-mg Bioperine®) reduced the use of naproxen by 84% (compared to 19% in placebo) in Iranian KOA patients and a further alternative (Theracurmin®; 10% of curcumin, 2% other curcuminoids such as demethoxycurcumin and isdemethoxycurcumin, 46% glycerin, 4% gum ghatti, and 38% of water; 180 mg of curcumin) reduced dependence on celecoxib in Japanese KOA patients (from ~70% to ~30% versus ~80 to ~60% in placebo; [294]). Recently, Heidari-Beni et al. [301] presented findings from a herbal formulation containing curcumin (300 mg), gingerols (7.5 mg) and piperine (3.75 mg), taken twice a day for 4 weeks. This formulation reduced PGE2 (see above text and Figure 1) of KOA patients to the same extent as Naproxen (250 mg capsules daily). There is significant mechanistic evidence to support these
Alternative terrestrial botanicals have shown some advantages for OA. Three studies have investigated avocado/soybean extracts and their potential in reducing NSAID and analgesics use. One large randomised control trial (n = 260) showed that after 30 days (and continued to day 90) of supplementation, the extracts (300 or 600 mg) reduced the daily intake of NSAID and analgesics compared to placebo. Furthermore, 71% (compared to 36% in placebo) of avocado/soybean extract participants reduced their daily intake by greater than 50%, [281]. Although it must be noted that the treatment was stopped in nine participants due to adverse events from the extract, however the authors did not statistically analyse incidence of adverse events of the remaining participants, but they were generally similar to placebo. These results were somewhat supported by a smaller (n = 31; part of a large cohort receiving a number of nutraceutical compounds) observational study showing that the proportion of OA patients using analgesics and NSAIDs dropped by 34% over 6 months consuming avocado/soybean extracts [282]. Although, in this large scale “real-world” (PEGASus) study cohort where analgesic and NSAID use was assessed by phone interview bi-monthly over 2 years, avocado/soybean extracts showed no effect on reducing medication use [313]. Recently, a 2-month supplementation of avocado/soybean unsaponifiables (n = 30; 300 mg daily) was compared to celecoxib (n = 30; 200 mg/day) for changes in a biomarker of cartilage breakdown (Cartilage oligomeric matrix protein; COMP). The results showed that both interventions reduced serum COMP levels with a tendency for greater improvements with avocado/soybean unsaponifiables (33.8% vs. 30.3%; p = 0.06; [283]). These data in addition to other mechanistic work show that avocado/soybean unsaponifiables can impact both inflammatory and structural protein biomarkers of OA pathology. Specifically they can inhibit IL-1, reduce production of stromelysin, IL-6, IL-8 and PGE-2, increase the expression of TGF-β and activate collagen synthesis [283, 314, 315, 316]. There is some debate over the efficacy of avocado/soybean extracts to alleviate analgesics and NSAID use but there is developing molecular evidence that they may elicit similar reductions on
Two studies investigated Ginger root extract formulations in OA NSAID use. Compared to 1% diclofenac gel, topical ginger extract (Plygersic gel) reduce KOOS variables (pain, symptoms etc.) equally after a six week intervention in mild radiographic KOA [296]. Further, oral consumption of a Ginger root extract formulation, compared (1) 50 mg of oral Diclofenac with Ginger 750, (2) Ginger 750 mg and (3) Diclofenac 50 mg for 12 weeks [297]. All interventions decreased pain and WOMAC variables but there was a reduction in rescue medication in the ginger groups, although this was not statically significant [297]. While these results are interesting, significantly more research is needed with larger more well controlled studies but there is molecular evidence to support these reported effects. Ginger root species can block the formation of inflammatory mediators such as thromboxane, leukotrienes and prostaglandins and inhibit COX and lipoxygenase in arachidonic acid metabolism [317, 318, 319, 320, 321, 322, 323, 324, 325] i.e. similar mechanisms to those presented in Figure 1.
\nFinally, the trade marked Pycnogenol® (pine bark extract; 100 mg) has been shown to reduces NSAID use by 58%, compared to only 1% in the placebo group in early-KOA patients over 12 weeks [286]. This resulted in reduced hospital admissions and days spent in hospital by 50% compared to placebo (n = 156; [286]). As with the above, Pycnogenol inhibits activation of NFκB pathway mediators, particularly, COX and pain-producing prostaglandins and also activates metabolomic compounds with anti-inflammatory bio-efficacy [326, 327, 328]. Again, these data are interesting and demonstrate good potential but require further
New Zealand Green Lipped Mussel (Perna canaliculus) lipid extracts have recently been investigated for their potentially benefits for OA symptoms. Moderate-to-severe hip and knee OA patients received 600 mg of Biolex®-GLM for 12 weeks or a placebo and were allowed to consume paracetamol for additional pain relief [285]. Participants consuming the placebo took more paracetamol each week of the 12 weeks resulting in a statically significant change at the final week (p = 0.001), however did not differ in NSAID equivalence score. This suggests that there may be some potential for Green Lipped Mussel to reduce analgesic medication, although less so than others mentioned herein. Again, Green Lipped Mussel appears to inhibit COX enzymes, competitive inhibition of arachidonic acid metabolism and reduce chronic inflammation [329].
\nA fish oil and Urtica dioica preparation has also been shown to reduce medication use in OA. A proprietary combination of omega-3 and omega-6 fatty acids, Urtica dioica (the common nettle), zinc and vitamin E (Phytalgic®) progressively reduced NSAID and analgesia use over a tree month period (n = 81; 6.5 Paracetamol 500 mg-Equivalent per week, compared to 16.5 in the placebo group; [284]). The authors ascribed this adaptation to the anti-inflammatory potential of the mineral composition, mainly from Urtica dioica within the formulation rather than the fish oil component [284]. This was most likely the case as a previous study showed no effect of cod liver oil an OA [330] and the articles referenced to show a mechanistic potential for fish oil components (n-3 and n-6 polyunsaturated fatty acids) have recently been retracted [331, 332].
\nThe marine red Algae species Lithothamnion corallioide, rich in sea water derived minerals including Calcium and Magnesium (AquaminF®), have recently been investigated for a potential impact on NSAID usage. In a randomised control trial of moderate-to-severe KOA patients that were regularly consuming NSAIDs, AquaminF (534 mg daily) was an effective agent for improving physical performance (six minuet walking distance), when NSAID use was intentionally reduced to 50% of previous consumption, but not when NSAID consumption was reduced to zero [298]. Furthermore, Lithothamnion (2668 mg) combined with seawater-derived Mg(OH)2 (268 mg) and pine bark extract (120 mg) reduced analgesic and NSAID use by 72% compared to Glucosamine Sulphate (2000 mg Daily dose) [299]. Mechanistically, Lithothamnion corallioide species appear to have the ability to inhibit the NFκB pathway, reduce inflammatory cytokines such as tumour necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1β) and COX2, along with reduced serum TNF-α [333, 334, 335, 336]. This suggested there is potential for Lithothamnion species to reduce the KOA-related drug dependency
These data are of considerable interest to those suffering from OA and medical practitioners concerned with the broader health impacts of pharmaceuticals use in OA patients. There appears to be a growing body of evidence suggesting that a variety of nutraceutical compounds, many in preparatory formulations, could provide some relief from the burden of NSAID and analgesic dependence, thus their associated side-effects. Currently the data are limited with respect to replication, sample size and duration, making conclusions about long term effectiveness difficult. The one potential exception is turmeric/curcumin extracts that in a recent meta-analysis it was shown that typically 1000 mg/day of curcumin was effective for improve OA symptoms (potentially better that NSAID) over 8-12 weeks - but the authors still call for significantly more research, specifically with increased sample size and better design quality [300].
\nWhile the precise molecular mechanisms of OA progression remain unclear, it appears to be exacerbated by the activation of NFκB signalling pathway, initiated by a host of mechanical and chemical stress stimuli, including excessive mechanical stress brought about by surplus body mass, proinflammatory cytokines and extracellular matrix degradation products [337, 338]. These actions reduce the amount of articular cartilage in the joints and degrade subchondral bone, thus induce pain and difficulty in movement. As a result, OA treatments focus on relieving pain and swelling, improving joint mobility, increasing musculoskeletal strength and minimising the disabling effects of the disease [339]. The NFκB signalling pathway and inflammatory mechanisms appear to be the molecular actions of the majority of the above nutraceuticals in combination with the inhibition of COX enzymes. These imply that their mechanism of action for pain relief (and therefore potential reduction in analgesic use) are via peripheral nociceptive action with little interaction through neuropathic mechanisms (unless through local inflammatory assault of nerve fibres).
\nAs discussed throughout, there appears to be even further benefit through combinations of nutraceuticals that may have an additive effects to reduce NSAID/analgesic use and are recommended [263]. However, additional work needs to be carried out to understand the individual effects of these combinations in addition to the synergistic impact. This requirement is evident through the work by Jacquet et al. [284] where it appears that the proposed benefit of the combination was not attributable to the ingredient that is mentioned and discussed firstly (fish oil), rather the benefit lies with Urtica dioica and mineral composition. These combinations are often proprietary formulations where the precise combinations are not publicly available. However, where this is not the case better understanding can be achieved through
In conclusion, this chapter has described and discussed chronic pain, specifically osteoarthritis, and presented evidence that specific nutraceuticals and combinations may have potential to either elicit the same pain reliving effect of NSAIDs and analgesics or reduce the dependency on these drugs. Specifically, the greatest evidence exists for the inclusion of turmeric/curcumin extracts as an mild-OA treatment adjunct to reduce NSAID consumption. Any reduction in the use of harmful pharmaceutical drugs should be a welcome inclusion to any treatment plan particularly when some nutraceuticals, that appear to interact with similar molecular pathways as the discussed analgesics, may be capable of offering such benefit. However, it must be noted that significantly more experimental evidence is required for a number of these bioactives and their propitiatory formulations before specific recommendations can be made.
\nThe authors have no acknowledgements to make.
\nThe authors declare no conflict of interest.
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