Selected papers on food, pharmaceutical, pharmacology, cosmetic, industrial, and analytical applications of cyclodextrins (CDs).
\\n\\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\\n\\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
\\n"}]',published:!0,mainMedia:null},components:[{type:"htmlEditorComponent",content:'IntechOpen is proud to announce that 179 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
\n\nThroughout the years, the list has named a total of 252 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\nReleased this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
\n'}],latestNews:[{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"},{slug:"oiv-awards-recognizes-intechopen-s-editors-20201127",title:"OIV Awards Recognizes IntechOpen's Editors"},{slug:"intechopen-joins-crossref-s-initiative-for-open-abstracts-i4oa-to-boost-the-discovery-of-research-20201005",title:"IntechOpen joins Crossref's Initiative for Open Abstracts (I4OA) to Boost the Discovery of Research"},{slug:"intechopen-hits-milestone-5-000-open-access-books-published-20200908",title:"IntechOpen hits milestone: 5,000 Open Access books published!"},{slug:"intechopen-books-hosted-on-the-mathworks-book-program-20200819",title:"IntechOpen Books Hosted on the MathWorks Book Program"},{slug:"intechopen-s-chapter-awarded-the-guenther-von-pannewitz-preis-2020-20200715",title:"IntechOpen's Chapter Awarded the Günther-von-Pannewitz-Preis 2020"}]},book:{item:{type:"book",id:"5332",leadTitle:null,fullTitle:"Vehicle Routing Problem",title:"Vehicle Routing Problem",subtitle:null,reviewType:"peer-reviewed",abstract:"The Vehicle Routing Problem (VRP) dates back to the end of the fifties of the last century when Dantzig and Ramser set the mathematical programming formulation and algorithmic approach to solve the problem of delivering gasoline to service stations. Since then the interest in VRP evolved from a small group of mathematicians to a broad range of researchers and practitioners from different disciplines who are involved in this field today. Nine chapters of this book present recent improvements, innovative ideas and concepts regarding the vehicle routing problem. It will be of interest to students, researchers and practitioners with knowledge of the main methods for the solution of the combinatorial optimization problems.",isbn:null,printIsbn:"978-953-7619-09-1",pdfIsbn:"978-953-51-6401-2",doi:"10.5772/64",price:119,priceEur:129,priceUsd:155,slug:"vehicle_routing_problem",numberOfPages:144,isOpenForSubmission:!1,isInWos:1,hash:"5780edf835fe9d95d60ebbc6eb00b38a",bookSignature:"Tonci Caric and Hrvoje Gold",publishedDate:"September 1st 2008",coverURL:"https://cdn.intechopen.com/books/images_new/5332.jpg",numberOfDownloads:23427,numberOfWosCitations:65,numberOfCrossrefCitations:55,numberOfDimensionsCitations:88,hasAltmetrics:0,numberOfTotalCitations:208,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"December 10th 2015",dateEndSecondStepPublish:"December 31st 2015",dateEndThirdStepPublish:"April 5th 2016",dateEndFourthStepPublish:"July 4th 2016",dateEndFifthStepPublish:"August 3rd 2016",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6,7",editedByType:"Edited by",kuFlag:!1,editors:[{id:"20440",title:"Prof.",name:"Tonči",middleName:null,surname:"Carić",slug:"tonci-caric",fullName:"Tonči Carić",profilePictureURL:"https://mts.intechopen.com/storage/users/20440/images/system/20440.jpg",biography:"Tonči Carić received his B.Sc. and the M.Sc. degree in Computer Science from Faculty of Electrical Engineering and Computing, University of Zagreb in 1993 and 2000 respectively. He received his Ph.D. degree in 2004 from Faculty of Transport and Traffic Engineering, University of Zagreb. He is currently working at the Department of Intelligent Transportation Systems, Faculty of Transport and Traffic Science, University of Zagreb as an Associate Professor and Head of Chair for Applied Computing. He participated as a researcher in R&D projects funded by European Commission, national research projects and professional projects in cooperation with industry. His main research interests are: combinatorial optimization, moving object databases and intelligent transportation systems. 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How long\nit takes you to fully recover from your surgery will depend on many things, including:Cyclodextrins (CDs) at times referred as Schardinger sugars or cycloamylose dextrins, were fortuitously discovered [1, 2] by Vielliers in 1891, who named these compounds as “cellulosing.” Later on Schardinger, who is considered the founder of CD chemistry, gave a detailed description about preparation and separation of CD and, more recently, Kurkov and Loftsson [3] also made significant contributions to CD science.
Franz Schardinger, studying microorganisms which play a role in the deterioration of foods and by action of cyclodextrinase-Bacillus macerans amylase on the starch, obtained two distinct crystalline substances with similar properties to the already known partial degradation products of starch, the dextrins, so he named them α-, and β-dextrin. The separation of the cycloalkyls may be carried out by selective precipitation by means of organic compounds or by high temperature chromatography on a cellulose column. French et al. demonstrated that CDs are cyclic oligosaccharides composed of several D-(+)-glucopyranose units in the form of a saddle [4]. In the second half of the 1930s, Freudenberg and his co-workers elucidated the cyclic structure of α-, and β-dextrin [5]. They consist of (α-1,4)-linked glucose units. A Greek letter preceding the abbreviation CD—for cyclodextrin—indicates the number of glucose units (α for 6, β for 7, and γ for 8) entering the composition of the cycloamylose. CDs constituted of less than 6 glucopyranose units cannot be formed due to steric hindrances [6]. Approximately, 1500 CD derivatives have been reported [7] in the literature.
CDs have a truncated cone appearance [7, 8, 9, 10, 11, 12], and a doughnut, toroidal- or cylinder-like shape, due to the spatial arrangement characteristic of the various functional groups of the glucose units. As a consequence of this conformation, all the secondary hydroxyl groups (corresponding to the C2 and C3 carbon atoms of the glucose units) are at one of the edges of the cavity, whereas the primary hydroxyls are in the other end of the cavity. Rotation of these –OH groups reduces the effective size of the cavity, making it have a more open conical truncated aspect [13] toward the side of the secondary hydroxyls (Figures 1 and 2).
Molecular structure of (a) α, (b) β, and (c) γ-CDs.
Steric structures of molecules from (a) α, (b) β, and (c) γ-CDs.
This spatial arrangement gives an apolar character to the interior of the cavity, whereas the presence of the –OH groups at the edges of the cone trunk makes them very water soluble. For instance, hydrophobic hosts will be housed inside the cavity because of the hydrophobic van der Waals type interactions, whereas simultaneously polar interactions can be established by the formation of hydrogen bridges between polar hosts and –OH of the primary hydroxyls. An endless number of physical and chemical processes [10, 14] are usually facilitated, that is, volatile substances may be stabilized by transforming in crystalline substances; oxygen-sensitive materials could find protection against oxidation; solubility and bioavailability of drugs could be improved [15, 16, 17, 18, 19, 20] by participating in controlled delivery processes.
CDs have been the subject of a large number of studies dealing with complexation and molecular catalysis [21, 22, 23, 24, 25], as well as studies about hydrophobic effects and fine-tune models of biological processes. In 1953, the first patent on CDs and complexes was registered, but until 1970, only small amounts of relatively pure CDs were produced for industrial use due to their high production cost. Although in the beginning it was erroneously thought that CDs were toxic, currently, it is difficult to imagine a world without CDs [3] due to their potential use [26]. The number of possible applications seems to be unlimited, i.e., computer-aided drug design, pharmaceutical, medical, biomedical and biotechnological, drug and gene delivery, foods, foods additives and ingredients, food processing, cosmetic, textiles, industrial and analytical. Currently, patents on CDs are counted by thousands.
An inherent interest surrounds these compounds due to their physical and chemicals properties [26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38]. The common feature of CDs is their ability to form inclusion complexes with a variety of molecules and ions, both in the solid state (crystalline substances) and in solution. As results of the structure of CDs, they can establish apolar-apolar interactions encapsulating other apolar molecules which may undergo structural changes [33, 34, 35, 36, 37, 38], acting as molecular capsules [27, 28, 29, 30, 31, 32]. However, the idea that one molecule could envelop another one to form a new compound (adduct, inclusion complex) was not accepted until X-ray diffraction showed the formation of an inclusion complex between α-CD and iodine [37]. They constitute a significant example of relatively simple organic compounds showing complex formation with other organic molecules. They are excellent models of enzymes that lead to their use as catalysts [21, 24, 39], both in enzymatic and non-enzymatic reactions. Additionally, they are natural products and readily available to most researchers.
It is accepted [18, 38, 40, 41, 42, 43] that the binding forces involved in complex formation are, in general:
van der Waals type interactions (or hydrophobic interactions) between the hydrophobic unit of the guest molecules and the CD cavity.
Hydrogen bond between the polar functional groups of the guest molecules and the hydroxyl groups of the CD.
Release of high energy water molecules from the cavity in the complex formation process.
Release of strain energy into the ring structure system of the CD.
The role of the hydrogen bond is not universal since stable complexes are formed with hosts such as benzene, which do not form hydrogen bonds.
Regardless of which type of stabilizing force is involved, the most important factors in determining the stability of the inclusion complex are [36, 40, 41, 42, 43, 44, 45]:
the geometric capability
polarity of the guest molecules
the medium
temperature
Geometric, rather than chemical factors, are critical in determining the type of “guest” molecules that can penetrate into the cavity. If the guest is too small, it passes easily through the cavity and the bond will be weak or will not occur. The formation of complexes with molecules significantly larger than the cavity is also possible, but only some limited groups or side chains penetrate into the CD cavity.
The stability of an inclusion complex also depends on the polarity of the “guest” molecule. Only substrates that are less polar than water may form inclusion complexes with the CDs. The stability of a complex is proportional to the hydrophobic character of the “guest” molecule. Highly hydrophilic molecules form complex CDs very weakly or do not complex at all.
On the other hand, stability depends heavily on the nature of the medium used for complexation. In principle, the inclusion complexes may be formed either in solution [46, 47, 48, 49] (generally carried out in the presence of water) or in the crystalline [40, 50, 51, 52] state. Although the formation of inclusion complexes also takes place [53] in an organic solvent, the guest molecules are weakly complexed. Additionally, although a 1:1 stoichiometry between the substrate and the CD molecule is typical [46, 54, 55, 56], with certain systems (Figure 3), 1:2 and 2:1 complex formations are possible. Experimentally determined formation constant can be the function (Figure 4) of the formation constants of the isomeric complexes [46]. In addition, substitution of one or more hydroxyls results in most cases in better water-soluble derivatives. For example, CDs can be polymerized [32, 36, 40, 42, 44, 45, 57] by suitable bio- or polyfunctional agents to oligomers, long-chain polymers or crosslinked or immobilized networks in various supports. Low molecular weight oligomeric CDs are readily soluble in water. Polymers (molecular mass over 10,000) are swollen gels which can be prepared in bead forms. The rigid structure of CDs “host” translates into well-defined and differentiated inclusion complex depending on the nature of the “guest” molecule.
Complexes of α-CDs and 1,4-disubstituted benzene [13].
Isomeric complexes from substrate and free ligand [55].
Finally, the stability of the inclusion complex, in general, decreases when temperature increases [46]. Enthalpy and entropy changes can be obtained from the temperature dependence of the equilibrium constant. An important issue, often overlooked in the CD field, is that the magnitudes of the standard free energy and entropy changes are dependent on the standard state chosen by the experimentalist.
In the last years, CDs and their derivatives have been used in a variety of fields of analytical chemistry, especially in analytical separations [45, 58, 59, 60, 61, 62, 63]. Spectral properties of CD and guest molecules can be altered due to the changes of the electrons distribution in the CD hole. CDs are used as reagent in different analyses such as UV-visible spectrophotometry, fluorescence [64, 65], phosphorescence [66, 67], and nuclear magnetic resonance methods [45, 68, 69].
The complexation of the analyte and/or the colored reagent can effectively change its properties. Among the most notable uses of this effect are: (i) enhancing the solubility of polar or non-polar analyte; (ii) enhancing the stability in polar or non-polar solution of reagents and colored complexes; (iii) increasing UV-visible absorption which improves the sensitivity of the colored reactions; and (iv) enhancing colored reactions selectivity. Luminescence techniques, in terms of fluorimetry and phosphorimetry, have reached a rapid development in routine analysis. However, many compounds luminesce very weakly in aqueous solution and the addition of CDs protects the excited (singlet or triplet) states of the possible dampers present in the solution since the rotation of the molecules is impeded due to the formation of the complex of inclusion with the result of a decrease in vibrational relaxation processes. The formation of inclusion complexes also increases the quantum fluorescence yield and hence the fluorescence intensities of numerous compounds. Sensitivity to certain characteristic reactions also increases.
CDs also increase the emission intensity of the chemiluminescent reactions. This improvement can be attributed to a number of factors, including an increase in the reaction rate and a greater efficiency in the process of excitation and protection of species that emit quenching phenomena. One of the most relevant applications of CDs is to allow the observation of phosphorescence at room temperature [67]. This is because they protect the excited triplet state of the molecules of the shock absorbers present in the solution, and in the case of molecular quenching phosphorescence. They are used as chiral reagents in NMR. In many cases, the formation of inclusion compounds modifies the general characteristics and chemical shifts of two enantiomers. Differences in the chemical shifts of two diastereoisomers can be used for the determination of the isomeric purity of the samples. The formation of inclusion complexes can very significantly modify the redox characteristics [13, 70, 71] of the included molecules. Voltammetric sensors capable of responding to anionic compounds have been developed. The changes produced after the complexation (selective interaction) allow the voltammetry to be used in the study of the complexation between CDs and organic molecules.
CDs increase the selectivity of chromatographic separations [72, 73, 74], because the separation process is more selective than that between the eluent and the stationary phase alone. In HPLC, the application of the CDs has achieved a spectacular success. Their incorporation into the mobile phase allows improving the separations, since they are soluble in water and provide reversible and selective complexation. In addition, they are stable and show no absorption in the UV-visible region of the electromagnetic spectrum. These characteristics mean that CDs are generally used in reverse phase separation processes, achieving the separation of isomers, diastereoisomers, and enantiomers [75, 76, 77, 78]. The high resolution obtained is due to the differences in the stability constants of the complexes in the mobile phase and the different adsorption of these complexes in the stationary phase. CDs may also be incorporated as support for the stationary phases. Capillary electrophoresis has also found use in chiral analytical separations [79, 80, 81, 82].
CDs have mainly been used as complexing agents to improve the aqueous solubility of molecules. This allows the use of CDs to reduce or prevent gastrointestinal or ocular irritation by lowering the local concentration of the free drug below the irritancy threshold. Also, unpleasant odor or taste of drugs can be hidden by complexation of the functional groups that produce them with CDs, occulting them from the sensory receptors [83, 84, 85], furthermore, reducing their hydrophobicity using CDs. Finally, CDs can increase percutaneous or rectal absorption of drugs and their derivatives can increase the guest molecule bioavailability [84]. Recently, CDs and their derivatives have been used in dispersed vehicle systems such as emulsions, microcapsules, microspheres, nanospheres, nanocapsules, liposomes, and beads [86]. Additionally, the host-guest property allows CDs to be used as building blocks in supramolecular chemistry [7]. Suvarna et al. [87] explain an insight in the use of CDs to increase the bioavailability to resolve the problem of solubility and stability of phytochemicals. The authors describe that some chemicals as quercetin, curcumin, arteminsinin, resveratrol or naringenin increased their bioavailability due to the inclusion complexes with CDs. Authors concluded that CDs need to be more explored to cover some molecules that have potential biological activity but have not been approached.
The encapsulation with CDs is gaining interest in different industries; this is reflected in the large number of publication and products related with it, such as drug delivery systems [7, 35]. This capacity of encapsulating compounds is used for a wide variety of things, among them is to protect the compounds, or to transport them to a target. This ability is due to the toroidal shape of CDs which makes possible to encapsulate hydrophobic molecules fully or partially in their cavity [14, 35]. This characteristic let the CDs being used for oral, sublingual, ocular, nasal, rectal, pulmonary, dermal, and other drug delivery systems, especially in systems of type 1/1 (one molecule per CD). The encapsulation with CDs enhanced the bioavailability of lipophilic drugs, as they are 17β-estradiol, androstenediol, clomipramine, and others. A limitation of CD in sublingual route is that the quantity used for a proper formulation is too large to be considered. This increase in the bioavailability is also observed in the oral route for drugs such as diltiazem, flufenamic acid, molsidomine, salbutamol, having all of them a sustained release [88].
In order to optimize pharmacotherapy, drug release should be controlled in accordance with the therapeutic purpose and the pharmacological properties of the active substances. In recent years, the interest regarding the control of rate or time of delivery has significantly increased [88]. The multifunctional characteristics of CDs allow them to be used in most drug delivery systems [84]. The design process of drug delivery systems is currently more focused on the oral route, in which the release of the drug can be controlled by dissolution, diffusion, osmosis, density or pH. Challa et al. [89] give several examples of different uses in oral delivery. The use of β-CD increased the bioavailability of ketoprofen, terfenadine, and griseofulvin; but, the same CD, also demonstrated higher intensity or longer duration of therapeutic activity in tolbutamide or terfenadine. Although there are different effects depending on the modified CD used, for example, the solubility and dissolution rate can be increased using HP-β-CD, for drugs as albendazole, ketoprofen, phenytoin, and gliclazide; or an improvement of hydrolysis stability γ-CD, for drugs as digoxin, camptothesin and paclitaxel. For oral administration, all CDs can be used because they are not toxic.
The improvement of the efficacy and bioavailability of poorly soluble drugs can be achieved by nanoparticles, which are stable systems that are used to create drug delivery systems [83]. Nanoparticles are 100–10,000 times smaller than human cells and their uses revolutionize diagnosis, treatment, therapeutic efficacy, and patient compliance [83, 90]. However, nanoparticles are limited by their low drug loading and entrapment ability, which compromises their safety and efficacy [84]. The use of CDs as a polymer increases the loading capacity of nanoparticle systems [89]. Furthermore, the optimal drug bioavailability and biodistribution can be achieved with a proper manipulation of physico-chemical and biological mechanisms, which can be provided by the hybrid functionalities of CD nanosystems [91]. A new class of colloidal polymer is nanosponges, which consist of solid nanoparticles with colloidal shape and nanocavities. Examples of nanosponges are those based on CDs. It should be noted that the type, number, and position of the substituent on the CD affect the complexation ability of nanosponges. Thus, it is crucial to know which CD derivative to use. Tejashri et al. [92] expose the use of CD to make nanosponge, and the use of it to load drugs and use as carriers. The crosslinking of CDs with compounds, as carbonyl or dicarboxylate, creates the different types of nanosponge, polyamide, carbonate, etc. Authors concluded that this novel class of CD-based nanosponge let drugs to be released in a controlled form at the target place, and its spherical shape let nanosponge to be administered as parental, aerosol, topical, tablets, and capsules forms.
In last years the application of CDs in the food-industry have increased mainly due to the use of them as a protective agent against oxygen, to protect flavor of volatile compounds, to enriched food with vitamins and color components (such as anthocyanins) or to stabilize them [93, 94]. Another advantage for the food industry is that CD are tasteless, odorless, and non-caloric saccharides, and that they have an antidiabetic effect due to their low glycemic index and their capability to decrease the glycemic index of the food, and also to improve the cholesterol index. Human gastrointestinal enzymes cannot digest them, so it can be used as a dietary fiber, which is fermented by microflora, what makes them a prebiotic compound. All these properties make them nutraceuticals and bioactive food supplements [95, 96]. López-Nicolás et al. [97] analyzed the positive effects of CDs in the encapsulation of antioxidant, and the repercussion on important factors as KF or pH values. They also reviewed the antioxidant capacity of CDs, but they concluded that there is a necessity of more studies in this aspect.
The cosmetic industry is looking for products with a good biological activity and adequate delivery on the skin [98]. The applications of CDs in cosmetics are similar to the pharmaceutical ones, e.g., stabilizing substances or increasing their solubility [99, 100, 101]. Centini et al. [98] associated ferulic acid, which is a photoprotector agent and an antioxidant compound, and CD. However, ferulic acid is not too much used due to the instability of it in the presence of air, UV-light, and heat; so, the aim of the work was to enhance the physico-chemical stability. The authors concluded that the complex ferulic acid/CD have a better photostability and do not generate degradation products. Buschmann and Schollmeyer [99] explained the use of CD against the vaporization of slow release of the volatile compounds in perfumes; or the opposite, they also explained the use of CD to eliminate undesired odors, such as mercapto derivate used in waving lotion. More applications will become possible when CDs price decreases. CDs can also be used in the textile industry as depots of cosmetic molecules providing new cosmetic formulations.
A more detailed picture of most recent selected applications in various areas, ranging from general reviews to inclusion complexes, metal and organometallic complexes, food, pharmaceutical, pharmacological, medical and biomedical, environmental chemistry, personal care and toiletry, industrial, nanotechnological, industrial and analytical applications to enzyme, biomimetic, bioactive assembles and recognition, as well as miscellaneous applications is compiled in Table 1, which gives an idea of the importance and relevance of the CDs field. Figure 5 shows the number of publications cited per year, whereas in Figure 6, the number of papers cited by journal for the most cited journal (number of references ≥2) appears. Emphasis is stressed on reviews and taking into account the high number of references available, the authors apologize for those they may have overlooked or inadvertently omitted.
Content | Authors | Refs. |
---|---|---|
General reviews | ||
Overview about the work carried out on CDs concerning with: the general characteristics of CDs and derivatives, the preparation and evaluation of inclusion complexes, the use of CDs in the preparation of drug delivery systems, and their use for the preparation of biomaterials and nanoparticles. | Duchêne and Bochot (2016) | [14] |
Comprehensive overview on the methods used for analysis of CDs and CD-derivatives. The paper intends to act as a guide in looking around the classical and modern instrumental analytical methods suitable for identification, characterization and determination of CDs themselves, CDs in finished products or even in biological samples. | Szente et al. (2016) | [2] |
Current review on various aspects of CDs with regard to their chemical characteristics, properties, approaches used for complexation, characterization techniques, uses along with and future potential. | Khan and Durakshan (2013) | [7] |
Pharmaceutical applications of CDs with an emphasis on their solubilizing properties, their tendency to self-assemble to form aggregates, CD ternary complexes, and their metabolism and pharmacokinetics. | Kurkov and Loftsson (2013) | [3] |
Overview about several aspects related to the physico-chemical properties of CDs and their potential applications illustrated by recent examples. | Venturini et al. (2008) | [102] |
Inclusion complexation and CDs: physicochemical parameters of the guest molecule and improvements in the molecule’s solubility, stability, taste, safety, bioavailability, etc. | Mosher and Thompson (2007) | [103] |
CDs and their use in industrial products, technologies and analytical methods. | Martin del Valle (2004) | [93] |
Overview about past, present, and future of CD research. Potential uses of CDs in pharmaceuticals, foods, cosmetics, and chemical products and technologies. | Szejtli (2004) | [26] |
CDs: structure, complex formation, drug solubility and non-conventional CD complexes. | Loftsson (2002) | [9] |
Scientific and technological aspects of CDs: from computational chemistry to industrial uses of CDs. | D’souza and Lipkowitz (1998) | [104] |
History (the three stages in the development of CD chemistry), fundamentals of CD chemistry and future trends. | Szejtli (1998) | [105] |
The properties and potential uses of CD derivatives: dimethyl- and dimethyl-βCD (DIMEB and TRIMEB). | Szejtli (1992) | [106] |
Catalyses by CDs leading to practical usages: covalent, non-covalent and asymmetric catalyses by CDs. | Bender and Komiyama (1978) | [107] |
Inclusion complexes | ||
The inclusion complex of oxyresveratrol in modified CDs: a thermodynamic, structural, physicochemical, fluorescent and computational study. | Matencio et al. (2017) | [108] |
Summary of method for inclusion complex formation of CD with its guests and its applications. | Cheirsilp and Rakmai (2016) | [42] |
Literature review to characterize the formation of inclusion complexes by different techniques in the solid and in the solution state complexation. | Maazaoui and Abderrahim (2015) | [44] |
Use of CDs as complexing agents to enhance the solubility of poorly soluble drugs and hence to resolve the many issues associated with developing and commercializing poorly water-soluble drugs. | Chaudhary and Patel (2013) | [16] |
Survey of crystal structures of pure CD hosts and CD inclusion compounds carried out during the last six years. The entries range from simple alkylated derivatives to elegant multi-substituted target CD molecules, with and without included guests. | Caira (2011) | [40] |
CD inclusion of four phenylurea herbicides: determination of complex stoichiometries and stability constants using solution 1H NMR spectroscopy. | Smith et al. (2010) | [69] |
Comparison of the inclusion complexation between host and guest in CD chemistry with the coordination interaction between central ion (Mx+) and ligands in coordination chemistry. | Song et al. (2009) | [36] |
Threading CDs molecules onto polymer chains to form crystalline inclusion complexes organized by non-covalent interactions. | Martinez and Gomez (2007) | [109] |
Practical considerations in development of solid dosage forms that contain CD. | Miller et al. (2007) | [110] |
CD inclusion complexes with a solvatochromic fluorescent probe: an undergraduate physical chemistry lab experiment to establish the solvatochromic nature of PRODAN and then use the changes in the emission spectra upon inclusion in β- or γ-CD to determine stoichiometry and formation constants for the complexes. | Baker et al. (2002) | [111] |
Some applications of CD/ substrate inclusion complexes. | Crini et al. (2001) | [8] |
Determination of thermodynamic parameters of the CD inclusion processes: an undergraduate physical chemistry lab experiment. | Valero et al. (1999) | [112] |
Complexation thermodynamics of CDs. | Rekharsky and Inoue (1998) | [113] |
Applications of CDs to pharmaceutical industry and chemical catalysis. Analytical applications are also considered, since CDs inclusion improves the sensitivity and selectivity of most analytical methods. | Muñoz-Botella et al. (1995) | [37] |
β-CD inclusion complexes with iodine: an advanced and inexpensive undergraduate chemistry experiment. | Diaz et al. (1994) | [114] |
Critical overview about past, present and future of CDs: properties, studies on CD inclusion compounds and its applications. | Davies et al. (1983) | [115] |
Metal and organometallic complexes | ||
Synthesis, reactivity and structural diversity of well-defined metal complexes derived essentially from native CDs. Structural motifs for metal complexes based on CDs: from monomeric species, dinuclear systems, homo- and heterometallic sandwich-type complexes to cylindrical, extended structures. | Prochowic et al. (2016) | [116] |
Overview of recent advances of CD catalyzed reactions, which is organized in the order of the following reaction types: the modified CD catalyzed organic reaction, CD catalyzed organic reaction of metal ion present, CD catalyzed organic reaction without metal ion, and CD catalyzed organic reactions in application of asymmetric synthesis and photochemical reactions. | Hong et al. (2015) | [117] |
Research and application of CDs and their derivatives in asymmetric and stereospecific syntheses, with their division into three main groups: (1) CDs promoting asymmetric and stereospecific catalysis in water; (2) CDs’ complexes with transition metals as asymmetric and stereospecific catalysts; and (3) CDs’ non-metallic derivatives as asymmetric and stereospecific catalysts. | Macaev and Boldescu (2015) | [118] |
Preparation and analysis of CD-based metal–organic frameworks: laboratory experiments adaptable for high school students. | Smith et al. (2015) | [49] |
Selectively functionalized CDs and their metal complexes: recent applications as chiral receptors and catalytic center in the mimicking of metalloenzymes. | Bellia et al. (2009) | [119] |
Metal complexing properties of native CDs (including deprotonation in alkaline medium) and a report on some recent results on composition and stability of metal–CD complexes. | Norkus (2009) | [120] |
CDs as supramolecular hosts for organometallic complexes. | Hapiot et al. (2006) | [121] |
Food applications | ||
Complexation of poorly water-soluble phytochemicals (flavonoids, phenolic derivatives, coumestans to triterpenes) with CDs to improve their aqueous solubility, stability, rate of dissolution and bioavailability. | Suvarna et al. (2017) | [87] |
CDs in food technology and human nutrition: benefits and limitations. The recent applications of CDs for reducing unwanted components, such as trans-fats, allergens, mycotoxins, acrylamides, bitter compounds, as well as in smart active packaging of foods are also overviewed. | Fenyvesi et al. (2016) | [95] |
History, chemistry, methods of complexation and application of CDs into different areas, particularly in the pharmaceutical and food industry. | Maazaoui and Abderrahim (2015) | [44] |
Properties, enzymatic production, and food applications of α-CD, as well as its differences with β- and γ-CDs. | Li et al. (2014) | [122] |
Studies on the complexes formed between several important types of antioxidant compounds and CDs. | López-Nicolás et al. (2014) | [97] |
Applications of CDs as food additives and in food processing: transport of previously nontransportable foods and prevention of the spread of microbial infections. | Martina et al. (2013) | [123] |
CDs as novel solutions for the food industry concerning with their role as dietary fiber, in food and drink with health-promoting additives, protect sensitive ingredients, improve taste and odor, or their positively influence to the texture and consistency of food. | Zipp (2012) | [96] |
Factors controlling flavors binding constants to CDs and their applications in foods. | Astray et al. (2010) | [124] |
CD encapsulation of essential oils and volatiles: methods for the preparation of inclusion complexes, analytical techniques and applications. | Cabral Marques (2010) | [33] |
Practical aspects of the utilization of CDs and CD inclusion compounds to food manufacture, focusing on the technical advantages of their use in food processing and as food additives. | Moreira da Silva (2009) | [125] |
Use of CDs in the food industry: properties from a technological point of view, such as solubility and their capability to form inclusion complexes are described. | Astray et al. (2009) | [94] |
Isolation and identification of native and branched-type (glucosylated and maltosylated) CDs in different enzyme- and heat-processed starch-containing food products. | Szente et al. (2006) | [35] |
Practical aspects of the utilization of CDs and CD complexes in the food industry: molecular encapsulation of lipophilic food ingredients, long-term storage stability and technological advantages and food processing technologies. | Szente and Szejtli (2004) | [126] |
CDs: application to food processing. | Yoshii (2004) | [127] |
Pharmaceutical applications Reviews | ||
CDs: history, chemical structure, synthesis, physicochemical properties, uses, complexation phenomenon, approaches for making inclusion complexes, and its characterisation, advantages of inclusion complexes, mechanism of drug release, regulatory status and its applications. | Kanaka Durga Devi et al. (2010) | [83] |
Basic science information and data on the development of drugs in CD-containing formulations. | Loftsson and Brewster (2010) | [128] |
Critical review about experimental methods for determination of the binding constant between CD and a guest molecule. | Funasaki et al. (2008) | [10] |
Historical development of CDs with emphasis on their use in pharmaceutical formulations. | Loftsson and Duchêne (2007) | [129] |
CD-based pharmaceutics: past, present and future applications. | Davis and Brewster (2004) | [130] |
CDs: structure, complex formation and drug solubility and non-conventional CD complexes. | Loftsson (2002) | [9] |
Main impetus for the research into CD-drug combinations. | Frömming and Szejtli (1994) | [131] |
Delivery release | ||
Application of CD nanosystems for oral drug delivery: strategies for the synthesis of these nanosystems, and their potential for the intelligent navigation of the gastrointestinal tract for optimal bioavailability and biodistribution. | Adeoye et al. (2017) | [91] |
CD-mediated hierarchical self-assembly and its potential in drug delivery applications. | Antoniuk and Amiel (2016) | [132] |
Supramolecular nanostructures based on CD and poly(ethylene oxide): syntheses, structural characterizations and applications for drug delivery. | Zheng and Wyman (2016) | [133] |
Recent advances in drug delivery techniques utilizing CDs, and cyclic oligosaccharides consisting of α-1,4-linked α-D-glucopyranose units. Especially, drug delivery system consisting of combination systems of CDs and functional materials such as dendrimer, liposome and PEG are introduced. | Arima et al. (2015) | [134] |
Relationship between CDs structure and physicochemical characteristics: self assembly and drug delivery. Importance of the nanoparticle technology preparation for the stability and application of this nanodevice. | Bonnet et al. (2015) | [135] |
CD-based carriers for delivery of chemotherapeutic cytotoxic anticancer drugs. | Gidwani and Vyas (2015) | [90] |
CD-based delivery systems for arthritic diseases: from development to experimental therapeutics. | Nascimento et al. (2015) | [136] |
A vision for CD nanoparticles in drug delivery systems and pharmaceutical applications. | Lakkakula and Krause (2014) | [137] |
CD containing biodegradable particles: from preparation to drug delivery applications. | Zafar et al. (2014) | [138] |
State of the art and recent advances in the construction of CD-based assemblies and their applications for controlled drug delivery. | Zhang and Ma (2013) | [139] |
CD in drug delivery: complexing agents, bioavailability and industrial applications. | Chordiya Mayur and Senthilkumaran (2012) | [86] |
Recent developments of CDs in drug delivery using various routes of administration. | Laza-Knoerr et al. (2010) | [140] |
Advantages of CD inclusion complexation, effects on important drug properties in formulation and applications in delivery systems (oral drug, rectal dug, nasal drug, transdermal drug, ocular drug, controlled and targeted drug, peptide and protein delivery, gene and oligonucleotide delivery, dermal and transdermal delivery, brain drug delivery or brain targetting). | Tiwari et al. (2010) | [84] |
CD-based supramolecular architectures: syntheses, structures, and applications for drug and gene delivery. | Li and Loh (2008) | [141] |
Applications of CDs and their derivatives in different areas of drug delivery: parenteral, oral, ophthalmic and nasal drug delivery. Other routes including dermal, rectal, sublingual and pulmonary delivery are also briefly addressed. | Rasheed et al. (2008) | [88] |
Applications and comparative benefits of use of CDs and their derivatives in the design of novel delivery systems like liposomes, microspheres, microcapsules, nanoparticles, CD grafted cellulosic fabric, hydrogels, nano- sponges, beads, nanogels/nanoassemblies and CD-containing polymers. | Vyas et al. (2008) | [142] |
The utility of CDs for enhancing oral bioavailability. | Carrier et al. (2007) | [143] |
CDs as cosmetic delivery systems: study of ferulic acid/ CD association complexes at the light of its possible use as sunscreen. | Centini et al. (2007) | [98] |
Effects of hydrophilic CDs on drug permeation through membranes and possible mechanism of action based on the current knowledge of the structural characteristics of water and the unstirred water layer juxtaposed to the membrane of interest. | Loftsson et al. (2007) | [144] |
Interesting findings and applications of CDs and their derivatives in different areas of drug delivery, particularly in protein and peptide drug delivery and gene delivery. Applications in the design of various novel delivery systems like liposomes, microspheres, microcapsules, and nanoparticles. | Challa et al. (2005) | [89] |
CDs in drug delivery. Pharmaceutical products worldwide containing drug/CD complexes on the market. | Loftsson et al. (2005) | [145] |
Recent findings and applications of both unmodified and modified CDs for in vivo drug delivery. Use of CDs for parenteral, oral, ophthalmic, and nasal drug delivery. Other routes including dermal, rectal, and pulmonary delivery are also briefly addressed. | Rajewski and Stella (1996) | [54] |
Carrier | ||
Potential therapeutic application of dendrimer/CD conjugates with targeting ligands as advanced carriers for gene and oligonucleotide drugs. | Arima et al. (2017) | [146] |
Drug carrier systems based on CD supramolecular assemblies and polymers: present and perspectives. | González-Gaitano et al. (2017) | [147] |
CD-based polymeric nanoparticles as efficient carriers for anticancer drugs. | Duchêne et al. (2016) | [148] |
Potential use of chemically modified CDs as high-performance drug carriers in drug delivery systems with emphasis on the more recent developments. | Rasheed et al. (2008) | [88] |
CD drug carrier systems: characteristics, improvements of drug properties by CD complexation and CD-based drug delivery systems. | Uekama et al. (1998) | [149] |
Solubilization and permeation | ||
CDs in pharmaceutical formulations: solubilization, binding constant, and complexation efficiency. | Jambhekar and Breen (2016) | [18] |
Use of CDs as complexing agents to enhance the solubility of poorly soluble drugs and issues associated with developing and commercializing poorly water soluble drugs. | Chaudhary and Patel (2014) | [16] |
Pharmaceutical applications of CDs: effects on drug permeation through biological membranes. | Loftsson and Brewster (2011) | [150] |
General background to the use of CD as solubilizers as well as highlight kinetic and thermodynamic tools and parameters useful in the study of drug solubilization by CDs. | Brewster and Loftsson (2007) | [15] |
CDs as solubilizers as well as highlight kinetic and thermodynamic tools and parameters useful in the study of drug solubilization | Loftsson and Brewster (1996) | [19] |
Protein | ||
Use of CDs and their derivatives as antiaggregant agents in a number of proteins and some multimeric enzymes. | Oliveri and Vecchio (2016) | [151] |
CD-based multivalent glycodisplays: covalent and supramolecular conjugates to assess carbohydrate–protein interactions. | Martínez et al. (2013) | [152] |
CD interactions with protein-like structures in order to describe their possible applications in the formulation of pharmaceutical proteins. | Varca et al. (2010) | [153] |
Encapsulation | ||
Encapsulation of CD/drug inclusion complex into conventional, deformable and double loaded liposomes: characteristics of these systems and advantages and disadvantages of each one. | Gharib et al. (2015) | [154] |
Encapsulation of biocides by CDs: toward synergistic effects against pathogens. | Nardello-Rataj and Leclercq (2014) | [34] |
Use of CDs as encapsulating agents for bioactive plant molecules in the pharmaceutical field. | Pinho et al. (2014) | [35] |
Excipients | ||
Background review for CDs used as excipients. | EMA/CHMP/333892/ (2013) | [155] |
CDs as functional excipients: methods to enhance complexation efficiency. | Loftsson and Brewster (2012) | [156] |
Formulations | ||
CDs in pharmaceutical formulations: structure and physicochemical properties, formation of complexes, and types of complex. | Jambhekar and Breen (2016) | [17] |
Evaluation of CDs drug complexes in pharmaceutical formulation: preparation of sodium valproate phenytoin sodium/ β-CD inclusion complex in a trial to stabilize the drug against moisture absorption and forming non-hygroscopic powders and preparation of phenytoin sodium/β-CD inclusion complex in a trial to stabilize the drug against moisture absorption and mask its bitter taste. | Akasha et al. (2014) | [157] |
CDs in topical drug formulations: drug delivery from aqueous CD solutions by diffusion and membrane controlled. | Loftsson and Masson, (2001) | [158] |
Miscellaneous | ||
Types of fluorophores which have been used for CD tagging: synthetic strategies used for the conjugation and pharmaceutical applications of these ‘visualized’ macrocycles including their use in photodynamic therapy. | Benkovics et al. (2017) | [159] |
CDs’ legacy as complexing agents and future prospects of this class of chemical entities in pharmaceutics as new active pharmaceutical ingredients. | di Cagno and Pio (2017) | [160] |
Use of CD in the different routes of drug administration. | Shimpi et al. (2005) | [161] |
Recent findings on the safety profiles of three natural CDs and several chemically modified CDs: stability against non-enzymatic and enzymatic degradations in various body fluids and tissue homogenates and their pharmacokinetics via parenteral, oral, transmucosal, and dermal routes of administration. | Irie and Hekama (1997) | [162] |
Pharmacology | ||
Production, physiochemical properties, pharmacokinetics, toxicity and applications of γ-CD and its derivatives. | Saokham et al. (2017) | [15] |
Interactions between CDs and cellular components: medical applications. | Leclercq (2016) | [163] |
Inclusion of terpenes in CDs: preparation, characterization and pharmacological approaches. | Lima et al. (2016) | [164] |
Self-assembly of CDs and their complexes in aqueous solutions. | Ryzhakov et al. (2016) | [48] |
Diagnostic utility of flow cytometry and improvement of rocuronium-induced anaphylaxis with the use of sugammadex. | Takazawa et al. (2016) | [165] |
Sugammadex for reversal of rocuronium-induced neuromuscular blockade in pediatric patients: a systematic review and meta-analysis. | Won et al. (2016) | [166] |
Improving the therapeutic response of analgesic drugs by CDs. | De Oliveira et al. (2015) | [167] |
Types of CDs, and their efficacy, physicochemical properties and transformation into nanoparticles with interesting in vitro and in vivo applications. | Lakkakula and Krause (2014) | [137] |
Potential therapeutic use of CDs and CD nanoparticles in neurodegenerative diseases, stroke, neuroinfections and brain tumors. | Vecsernyés et al. (2014) | [168] |
Basic and clinical pharmacology of sulfobutylether-β-CD. | Loftsson and Brewster (2010) | [128] |
Basic and clinical pharmacology of sulfobutylether-β-CD. | Luke et al. (2010) | [169] |
CD introduction to anesthesia practice: form, function, and application. | Welliver (2007) | [170] |
Findings on the safety profiles of three natural CDs and several chemically modified. | Irie and Uekama (1997) | [162] |
Medical and biomedical | ||
Key features of the CDs therapeutic discovery. Application of computational chemistry approaches such as QSAR/QSPR, molecular docking, and molecular/quantum mechanics for modeling of CD-drug system. | Abdolmaleki et al. (2017) | [171] |
Recent development of copolymeric delivery system for anticancer agents based on CD derivatives. | Feng et al. (2016) | [172] |
General features and applications of CDs and their interactions with isolated biomolecules leading to the formation of inclusion or exclusion complexes: potential medical applications. | Leclercq (2016) | [163] |
Data on the general properties and complexing ability of CDs and assessment methods (phase solubility, DSC tests and X-ray diffraction, FTIR spectra). | Radu et al. (2016) | [173] |
CD interactions with protein-like structures: possible applications in the formulation of pharmaceutical proteins. | Vecsernyés et al. (2014) | [168] |
Amphiphilic CDs and their applications: preparation of nanoparticles based on amphiphilic CDs for biomedical applications. | Parrot-Lopez et al. (2010) | [174] |
A supramolecular approach to medicinal chemistry: essential roles played by intermolecular forces in mediating the interactions between chemical molecules and biological systems. | Smith (2005) | [175] |
Medicinal applications of CDs: improvement of drug properties, use of drug/CD complexes, CDs in tabletting and direct treatment with CDs. | Szejtli (1994) | [176] |
Environmental Chemistry and Applications | ||
Nanosponge CD polyurethanes and their modification with nanomaterials for the removal of pollutants from waste water. | Leudjo Taka et al. (2017) | [177] |
Progress in the immobilization of β-CD and their application in adsorption of environmental pollutants. | Han et al. (2016) | [178] |
Interactions of CDs and their derivatives with toxic organophosphorus compounds. | Letort et al. (2016) | [179] |
CD inclusion of four phenylurea herbicides: determination of complex stoichiometries and stability constants using solution 1H NMR spectroscopy. | Smith et al. (2010) | [69] |
Fluorescence spectroscopy as a tool to study the properties of CD host-guest complexes. Overview of recent studies concerned with exploiting the properties of CDs and their inclusion complexes to study energy transfer through the use of photochemical antennas and the development of chemical and environmental sensors. | Fakayode et al. (2007) | [27] |
Synthesis and applications of adsorbents containing CDs in the field of chromatographic separations and in waste water treatment. | Crini and Morcellet (2002) | [180] |
Personal care and toiletry | ||
CDs as cosmetic delivery system: study of ferulic acid/CD association complexes. | Centini et al. (2007) | [98] |
Inclusion complex formation of CD with its guest and their applications in foods and flavors, personal care and toiletry, environment protection, pharmaceuticals among others. | Cheirsilp and Rakmai (2016) | [42] |
Possible applications of CDs in cosmetic products and some examples of their present uses. | Buschmann and Schollmeyer (2002) | [99] |
Industrial applications | ||
Enabling technologies and green processes in CD chemistry: microwaves, ultrasound and ball mills have become irreplaceable tools in the synthesis of CD derivatives. Examples of sonochemical selective modification of native α-, β- and γ-CDs including heterogeneous phase Pd- and Cu-catalysed hydrogenations and couplings. | Cravotto et al. (2016) | [181] |
Major fields of enzyme application and overview on previous protein engineering studies wherein natural enzymes were modified to meet the operational conditions required for industrial application. | Jemli et al. (2016) | [24] |
Applications of CDs in medical textiles: general data properties and complexing ability of CDs and assessment methods (phase solubility, DSC tests and X-ray diffraction, FTIR spectra, analytical method). | Radu et al. (2016) | [173] |
Applications of CDs in various industrial products, technologies, analytical and chemical processes and recent industrial advancements. | Sharma and Baldi (2016) | [182] |
General features of β-CD and their applications in the textile industry: attachment technique of β-CD to the textile’s surface. | Bhaskara-Amrit et al. (2011) | [183] |
CDs in pharmaceutics, cosmetics, and biomedicine: current and future industrial applications. | Bilensoy (2011) | [184] |
Role of CDs in the textile chemical technology: remove the surfactants from the material or to inactivate them in liquid phase, to intensify the enzyme processes or as balancers in dyeing with reactive pigments. | Grigoriu and Popescu (2011) | [185] |
Amphiphilic CDs and their applications. Preparation of nanoparticles based on amphiphilic CDs for biomedical applications. | Parrot-Lopez et al. (2010) | [174] |
Applications of CDs in pharmaceuticals with a major emphasis on drug delivery systems. Utility in a variety of foods, flavors cosmetics, packaging and textiles. | Singh et al. (2002) | [186] |
Applications of CDs in pharmaceuticals, foods and flavours, cosmetics, chemical industry, agricultural industry and adhesives, coatings and other polymers. | Arenskötter et al. (2001) | [187] |
Industrial applications of CDs. Production and analysis of complexes. | Hedges (1998) | [188] |
Utilization of CDs in industrial products and processes: (i) textiles, fibers and papers; (ii) foods and cosmetics; (iii) plastics and rubber; (iv) photographic and recording materials; (v) biotechnology and (vi) environmental protection. | Szejtli (1997) | [189] |
Overview about industrial uses of CDs and their derivatives. | Duchêne and Wouessidjewe (1992) | [190] |
CD inclusion compounds in research and industry: production of pharmaceuticals, pesticides, foodstuffs, and toilet articles among others. | Saenger (1980) | [191] |
Nano | ||
General overview of CDs and pharmaceutical nanotechnology in oral delivery systems. Strategies for the synthesis of these nanosystems, and their potential for the intelligent navigation of the gastrointestinal tract for optimal bioavailability and biodistribution. | Adeoye and Cabral-Marques (2017) | [91] |
Nanosponge CD polyurethanes and their modification with nanomaterials for the removal of pollutants from waste water. | Leudjo et al. (2017) | [177] |
CD-based supramolecular host–guest interactions for engineering supramolecular nanoparticles: biomedical applications. | Mejia-Ariza et al. (2017) | [192] |
CD-based polymeric nanoparticles as efficient carriers for anticancer drugs. | Duchene et al. (2016) | [148] |
CD-based nanosponges: a versatile platform for cancer nanotherapeutics development. | Swanimathan et al. (2016) | [193] |
Supramolecular nanostructures based on CD and poly(ethylene oxide): syntheses, structural characterizations and applications for drug delivery. | Zheng and Wyman (2016) | [133] |
Nano-sized CD-based molecularly imprinted polymer adsorbents for perfluorinated compounds. | Karoyo and Wilson (2015) | [194] |
Overall view of the diversity of designs of CD-based supramolecular nanosystems with a special focus on the advances materialized in the last five years, including clinical trials. | Simoes et al. (2015) | [195] |
Recent advances in the construction of nanoassemblies driven by CD-based inclusion complexation and their application in biomedical and biomimetic fields. | Kang et al. (2014) | [196] |
A vision for CD nanoparticles in drug delivery systems and pharmaceutical applications. | Lakkakula and Krause (2014) | [137] |
Approaches tested to synthesize nano- to macro-size covalently cross-linked CD networks: (i) direct cross-linking through condensation with di- or multifunctional reagents, (ii) copolymerization of CD derivatives with acrylic/vinyl monomers, and (iii) grafting of CDs to preformed medical devices. | Concheiro and Alvarez-Lorenzo (2013) | [197] |
Development of nanosponges as drug delivery systems, with special reference to CD based nanosponges. | Tejashri et al. (2013) | [92] |
Preparation, characterization and advantages for pharmaceutical and biomedical applications of CD-based nanogels. | Moya-Ortega et al. (2012) | [198] |
Formation and applications of CD nanoaggregates induced by guest molecules, the concerned thermodynamics behind the process and the effect of concentration of the guest molecules on the morphology of the aggregates. | Purkayastha et al. (2012) | [199] |
Approaches employed in delivering drugs to the central nervous system. Changes in blood-brain barrier function in several neurological disorders. | Martín-Banderas et al. (2011) | [200] |
Fabrication technologies of supramolecular systems including nanoplatforms and hydrogels as well as their applications in nanomedicine and pharmaceutical sciences. | Zhang and Ma (2013) | [139] |
Classification, physicochemical properties, efficacy and safety of nanoparticles prepared from different amphiphilic CDs are discussed in light of the current literature work with in vitro and in vivo findings. | Bilensoy and Hincal (2009) | [201] |
Analytical and physicochemical applications | ||
Reviews | ||
Classical and modern instrumental analytical methods suitable for identification, characterization and determination of CDs themselves, CDs in finished products or even in biological samples. | Szente et al. (2016) | [2] |
CDs in in sample preparation, sensitivity and selectivity improvement, enantio-separation, creating single-molecule sensors, and automatizing DNA sequencing. | Szente and Szeman (2013) | [28] |
CDs: from molecular recognition to CDs as enzyme models. Reactivity and chemistry, chromatography, X-ray, NMR plus other physicochemical methods, as well as model calculations, rotaxane and catenane structures, and applications in the pharmaceutical industry are overviewed. | Dodziuk (2006) | [202] |
Use of CDs in major areas of analytical chemistry such as chromatography, electrophoresis, spectroscopy, electrochemistry and as analytical sensors. | Mosinger et al. (2001) | [203] |
Role of CDs in three of the major areas of modern instrumental analysis: separations, spectroscopy and electrochemical analysis. | Armstrong (1998) | [204] |
Chirality | ||
CD-functionalized monolithic capillary columns: preparation and chiral applications. | Adly et al. (2016) | [205] |
Recent developments in CD functionalized monolithic columns for the enantioseparation of chiral drugs. | Guo et al. (2016) | [206] |
Advances on the use of CDs in the chiral analysis of drugs by capillary electrophoresis. | Saz and Marina (2016) | [80] |
Recent contributions to the understanding of the binding mechanism between chiral selectors and selectands in analytical enantioseparations including polysaccharide derivatives, CDs, cyclofructans, macrocyclic glycopeptides, proteins, brush-type selectors, ion-exchangers, polymers, crown ethers, ligand-exchangers, molecular micelles, ionic liquids, metal-organic frameworks and nucleotide-derived selectors. | Scriba (2016) | [77] |
Development of cationic CDs for chiral separation. Update of the research endeavors of synthetic and analytical chemists in evaluating enantioselectivity of cationic CDs using different analytical methods and the study of the chiral recognition mechanism. | Zhou and Scriba (2016) | [75] |
Advances in enantiomeric resolution on monolithic chiral stationary phases in liquid chromatography and electrochromatography. | Al-Othman et al. (2014) | [207] |
Recent examples of mechanistic aspects of capillary enantioseparations with regard to mathematical modeling of enantioseparations, investigations of the analyte-complex structures as well as new chiral selectors and applications of chiral analyses by CE and CEC. | Jac and Scriba (2013) | [208] |
Review of the latest advances in developing modified CDs as chiral selectors for various chromatographic and electromigration techniques. | Tang et al. (2013) | [76] |
Chiral analysis of amphetamines, methadone and metabolites in biological samples by electrodriven methods. | Mandrioli et al. (2011) | [209] |
The growth and applications of CDs as chiral discriminator. | Pathak and Pathak (2008) | [210] |
CDs in capillary electrophoresis enantioseparations: recent developments and applications. | Scriba (2008) | [90] |
Separation of enantiomeric barbiturates by capillary electrophoresis using a CD containing run buffer: a laboratory experiments for degree students. | Contradi et al. (1997) | [82] |
Complexes characterization | ||
Physicochemical characterization of CD-drug interactions in the solid state and the effect of water on these interactions. | Ogawa and Takahashi (2015) | [52] |
Analytical techniques for characterization of CD complexes in the solid state. | Mura (2015) | [51] |
Analytical tools which can be employed for the characterization of drug-CD inclusion complexes in solution, with emphasis on their respective potential merits, disadvantages and limits. | Mura (2014) | [47] |
Surfactant-CD host-guest association: fundamentals, drawbacks and advantages of techniques commonly used to obtain insights on the structural and bulk solutions changes resulting from host-guest association mechanism, and corresponding methods for binding quantification. | Valente and Söderman (2014) | [30] |
CD inclusion complexes probed by NMR techniques. | Pessine et al. (2012) | [45] |
A literature review of CD inclusion complexes characterization: X-ray diffraction, infrared spectroscopy and nuclear magnetic resonance. | Takahashi et al. (2012) | [211] |
A literature review of CD inclusion complexes characterization: differential scanning calorimetry and thermogravimetry. | Takahashi et al. (2012) | [68] |
A bilogarithmic method for the spectrophotometric evaluation of stability constants of 1:1 weak complexes from mole ratio data. | Boccio et al. (2006) | [212] |
NMR studies of CDs and CD complexes. Comprehensive overview about the most important approaches to structural problems with CDs, mainly in solution. | Schneider et al. (1998) | [213] |
The stability of CD complexes in solution: binding equilibria and kinetics, strengths and structures of CD complexes, the sources of CD complex stability and prediction of CD complex stability. | Connors (1997) | [46] |
Separation Methods | ||
State-of-the-art applications of CDs as functional monomers in molecular imprinting techniques. | Lay et al. (2016) | [214] |
CDs in capillary electrophoresis: recent contributions, practical uses (e.g. solute-CD binding constant estimation and further potentials), developments and applications (mainly chiral and achiral analysis). Recent developments and new trends. | Escuder-Gilabert et al. (2014) | [79] |
Separation processes in the presence of CDs using molecular imprinting technology and ionic liquid cooperating approach. | Zhang et al. (2011) | [59] |
Role of CDs in chromatography. Influence of The formation the physicochemical parameters of the guest molecule (adsorption capacity, polarity, hydrophobicity, etc.). | Cserhat and Forgaes (2003) | [71] |
Summary of the information concerning the synthesis of materials containing CDs and general overview of the different possible applications of CDs as sorbents in the field of separation techniques. | Crini and Morcellet (2002) | [180] |
CDs as a versatile tool in separation science. The techniques examined include gel electrophoresis, isotachophoresis, isoelectric focusing, preparative scale electrophoretic techniques, thin-layer chromatography, electrochemically modulated liquid chromatography, use of monolithic media in liquid chromatography, microdialysis, separation on hollow fibers, foam flotation enrichment, solid- and liquid-phase extractions, countercurrent chromatography, separation through liquid and composite membranes, and CD applications in molecularly imprinted polymers. | Schneiderman and Stalcup (2000) | [61] |
Utilization of CDs and their derivatives in gas-liquid and gas-solid-, gel-, inclusion-, thin-layer-, affinity-, and high performance liquid chromatography. | Szejtli (1987) | [215] |
Applications of CDs in chromatographic separations and purification methods. | Hinze (1981) | [73] |
Spectrofluorometric Methods | ||
Spectrofluorometric analytical applications of CDs based on host-inclusion complex. | Elbashir et al. (2014) | [64] |
Room temperature phosphorescence in CDs: analytical applications. | Muñoz de la Peña et al. (2000) | [66] |
Electrochemical Methods | ||
Advantages and detecting mechanism of electrochemical sensors based on CDs functionalized materials, and recent advances for CDs-based materials (including CDs/carbon nanotubes, CDs/graphene, CDs/conducting polymers and other CDs-based nanomaterials) in electrochemical sensing. | Zhu et al. (2016) | [70] |
Substrate/analyte solubilization and stabilization to the development of CD based sensors and detectors. | Szente and Szejtli (1998) | [216] |
State of the art of the electrochemistry of α-, β-, and γ-CDs and CD inclusion complexes and their polarographic and voltammetric assay. | Bersier et al. (1991) | [71] |
Enzyme—Biomimetic-Bioactive assemblies recognition | ||
General overview of three different categories of CD-based artificial enzymes including metal free CD-based artificial enzymes, CD-based artificial metalloenzymes and CD-based artificial enzymes with computational design, focusing on their rate acceleration factor. | Aghahosseini and Ramazani (2016) | [21] |
Major fields of enzyme application and overview on previous protein engineering studies wherein natural enzymes were modified to meet the operational conditions required for industrial application. | Jemli et al. (2016) | [24] |
Macromolecules based on recognition between CD and guest molecules: synthesis, properties and functions. | Liu et al. (2015) | [217] |
Representative contributions in the construction and the structural characteristics of CD-based supramolecular assemblies and their interactions with biologically important substrates. | Chen and Liu (2010) | [218] |
New chemistry based on the principles used by Nature: biomimetic chemistry. | Breslow (2009) | [23] |
Literature overview on reactions in which CDs bind substrates and then either catalyze their reactions or mimic a step in an enzymatic catalytic sequence. | Breslow and Dong (1998) | [22] |
Adjusting the lock and adjusting the key in CD chemistry. An introduction in biomimetic chemistry. | Breslow (1980) | [219] |
Miscellaneous | ||
Functioning via host–guest interactions: achievement of selective molecular adhesion, self-healing, toughness, and actuation properties. These functions have been achieved by reversible bond formation with CDs. | Takachima and Harada (2017) | [29] |
Qualitative and quantitative analysis of research outputs on molecular modeling in CDs. | Zhao et al. (2017) | [220] |
Supramolecular polymer assembly in aqueous solution arising from CD host-guest complexation. Effects of such complexation on properties at the molecular and macroscopic levels. | Wang et al. (2016) | [32] |
Superstructures with CDs: chemistry and applications. | Wenz and Monflier (2016) | [221] |
Synthesis of CD half-channels derived by per-functionalization of the CD primary positions and their activity as channels assessed by the bilayer clamp technique. | Chui and Fyles (2014) | [222] |
Construction of supramolecular structures of CDs with some polymers (polyrotaxanes) and formation of supramolecular oligomers and polymers formed by CD derivatives. | Harada et al. (2009) | [223] |
Systematic analysis of methods that are available for modification of CDs. The focus is on methods for transformation where the number and the exact positions of modifications are ascertained and pure compounds with unambiguous structures are obtained. | Khan et al. (1998) | [224] |
Applications of computational chemistry to the study of CDs: molecular modeling, structural features of CDs, dynamical aspects of CD structure and computational studies of host−guest complexation. | Lipkowitz (1998) | [225] |
CD-based catenanes and rotaxanes. | Nepogodiev et al. (1998) | [226, 227] |
Organic reactions mediated by CDs: effect in solid CD complexes. | Takahashi (1998) | [228] |
Selected papers on food, pharmaceutical, pharmacology, cosmetic, industrial, and analytical applications of cyclodextrins (CDs).
Number of publications cited per year.
Number of papers cited by journal.
Currently, there are a large number of drugs with poor solubility, bioavailability, permeability issues, undesirable properties as taste and odor, and irritation potential, and CDs can become an useful tool for optimizing drugs problematic [84]. Additionally, new uses of cyclodextrins are being explored, in different fields as nanoparticles, liposome and microsphere. The ability of making inclusion complexes with drugs makes CDs have a great future, as reflected by the rising number of publications and patents having been filed. Some researchers also believe that there will be more a still wider use for CDs as the knowledge about their properties increase [7]. The studies of CD-based nanosystems have recently increased, as they become platforms providing pharmacokinetic and formulation design efficiency without posing security problems [91]. CDs are also generating interest for gene therapy and exploration of non-viral methods, probably for the difficulties in viral gene delivery [7]. A new area which is going to increase, is the study of the effects of the environment in the reactivity between CD-guest molecules [115]. The creation of new types of CD is going to enhance due to the wide range of possibilities in the treatments of atherosclerosis, cancer, and degenerative brain disease that are considered lethal disease [160]. CDs will surprise us in the future with not predictable uses [184].
Pegvisomant is the only available GH antagonist. The history of pegvisomant development is an example of how research can be surprising. By combining site-specific mutation on the GH gene, researchers were looking for a long-acting GH treatment. However, researchers were surprised to find with the in vivo analysis an IGF1 reduction in mice treated with the modified GH molecule obtained. It was the beginning of pegvisomant history.
\nGH three-dimensional structure contains two disulphide bridges and four helices which are arranged in an “up-up-down-down” topology. Helices 1, 2, 3, and 4 are located between residues 9–34, 72–92, 106–128, and 155–184, respectively (Figure 1) [1]. Helix 3 is the key to promote a growth activity. In this helix, approximately 20 amino acids are arranged in an amphiphilic orientation. Among them, three amino acids do not enable an ideal amphiphilic helix [2]. When modifying these three amino acids, researchers wanted to generate a perfect amphiphilic helix 3 and hypothesised that it would enhance GH activity. Surprisingly, transgenic mice expressing this modified GH analog had decreased circulating IGF1 concentrations. It was the first report of a GH antagonist [3]. Further single amino acid substitutions demonstrated that glycine at position 120 of human GH was critical for the growth-promoting activity of the respective molecule. Crystallography studies demonstrated that this mutation of the glycine to a lysine at position 120 (G120K) of GH led to a defect of GHR dimerisation which is essential for GH transduction signal [4].
\nTwo-dimensional representation of the structure of human GH (adapted from de Vos et al.) [4].
However, because of its small size (22 kDa), GH is rapidly cleared by the kidneys and/or endocytosis as a GH/GHR complex. Indeed, the addition of polyethylene glycol (PEG) (5 kDa) increased the serum half-life from 30 min to 2 days. At this stage, we had a G120K-PEG GH molecule. However, the perfect GH antagonist was not yet found because the addition of PEG led to a decrease of binding affinity for site 1 (which is the first binding site of the GH molecule on the GH receptor). To circumvent this problem, mutagenesis of binding site 1 was considered. In the meantime, Cunningham and Wells published a more potent GH analog with eight amino acid substitutions in site 1 of the GH molecule. These eight mutations were introduced in the G120K-PEG GH molecule [5]. This molecule proved to maintain binding affinity for binding site 1 of GHR, antagonising properties of GHR with a long half-life. That was the birth of pegvisomant.
\nPegvisomant/GHR interaction has been more precisely studied. Primary studies suggest that pegvisomant binds to one GHR and prevents GHR dimerisation because of the G120K mutation which prevents binding to site 2. However, further studies show that pegvisomant induces GHR dimerisation with disulphide linkage and induces internalisation, as GH do. However, activation of jak kinase and stat 5 is less important because the conformation changes after pegvisomant binding is different with a less functional dimerisation [6, 7]. Moreover, internalisation after pegvisomant binding induces a different intracellular trafficking, with an increase of degradation of GHR, a decrease of GHR expression on cellular membrane, and a decrease of nuclear localisation of GHR [8].
\nMoreover, it appears that the eight mutations within site 1 do not increase affinity to GHR but to the GH binding protein and allow the dimerisation of GHR despite the pegylation (Figure 2) [7]. Reducing site 1 binding affinity, high doses of pegvisomant are necessary to antagonise GH action.
\nBinding representation of GH and pegvisomant (B2036-PEG) on GH receptor and schematic effect [1]. GH binds to GHBP and to binding site 1 and 2, inducing a conformational change of GHR, a jak/stat phosphorylation, and internalisation [2]. Pegvisomant binds to GHBP, and the complex binds to site 1 and site 2, inducing a less functional dimerization, a diminution of jak/stat phosphorylation, and a different intracellular trafficking with an increase of GH receptor degradation (adapted from Ross et al.) [6].
In the phase I study, 36 young volunteers received a single injection of either the placebo or pegvisomant (0.03, 0.1, 0.3, or 1.0 mg/kg). All doses were well tolerated, with no severe adverse events. IGF1 decreased significantly in all groups with a pegvisomant dose above 0.1 mg/kg (P < 0.001 vs. placebo) [9].
\nIn the phase II study, 46 patients with active acromegaly were randomised and received the placebo, 30 or 80 mg of pegvisomant once a week for 6 weeks. If IGF1 levels were unchanged in the placebo group, it decreased by 31 ± 6.7% in the 80 mg groups (P < 0.001). There was a dose-related decrease in serum IGF1. However, only three patients have a normal serum IGF1. Pharmacokinetic study evaluated pegvisomant half-life at 70 h [10]. Because of the low efficacy of pegvisomant in phase II and the half-life of 70 h, it was decided to give pegvisomant daily in phase III.
\nThe phase III study on 112 patients with acromegaly showed the efficacy of pegvisomant on serum IGF1 reduction and clinical improvement. This double-blind study showed a decrease of IGF1 from the baseline by 26.7 ± 27.9%, 50.1 ± 26.7%, and 62.5 ± 21.3% in the groups that received 10 mg, 15 mg, and 20 mg of pegvisomant per day, respectively (P < 0.001 for the comparison of each pegvisomant group with placebo). In these groups, 54%, 81%, and 89% had a normalised IGF1 at 12 weeks. Among patients treated with 15 mg or 20 mg of pegvisomant per day, there were significant decreases in clinical symptoms such as ring size, soft tissue swelling, the degree of excessive perspiration, and fatigue. Quality of life improved in all groups. Tumour volume was similar before pegvisomant and at 12 weeks [11]. One year later, van der Lely et al. published the extension of this study, with 152 patients on pegvisomant at 18 months; 97% of patient normalised serum IGF1 (Table 1) [12].
\n\n | N (female) | \nIGF1 before pegvisomant % ULN | \nMedian exposure time (months) | \nMedian dose mg/day (min max) | \nMonotherapy (% of patients) | \nNormal IGF1 (% of patients) | \nTumour enlargement (% of patients) | \nLiver enzyme elevation (% of patients) | \n
---|---|---|---|---|---|---|---|---|
Boguszewski et al. [14] | \n109 (61) | \n209 (99–637) | \n30.5 | \n10 (10–30) | \n11 | \n74.1% | \n6 | \n9.2 | \n
Basavilbaso et al. [33] | \n75 (51) | \n240 (125–700) | \n27 | \n12 (3–30) | \n45 | \n63% | \n9.8 | \n9.3 | \n
Buchfelder et al. [13] | \n2090 | \nNA | \n91.2 | \n18.9 | \nNA | \n73 | \n2.2 | \n3 | \n
Van der Lely et al. [12] | \n90 | \nNA | \n18 | \n19.6 | \n100 | \n97 | \n1.3 | \n1.3 | \n
Garcia et al. [18] | \n42 | \nNA | \nNA | \nNA | \nNA | \n58 | \nNA | \nNA | \n
Rostomyan et al. [19] | \n37 | \nNA | \nNA | \nNA | \nNA | \n51 | \nNA | \nNA | \n
Main study of pegvisomant efficacy and adverse events in real life.
NA: not available; ULN: Upper limit normal.
The ACROSTUDY is the largest international, noninterventional study of acromegaly patients treated by pegvisomant. Two thousand and ninety patients were analysed between 2004 and 2016. When starting pegvisomant, 89% of patients had an IGF1 above the upper limit of normal (ULN), previously treated by surgery, radiotherapy, medical therapy, or a combination of the three. After 10 years, 73% of patients had a normal IGF1 with a median dose of pegvisomant 18.9 mg/day (Table 1) [13].
\nA recent study evaluated the efficacy in real life. A Brazilian multicentre study of 109 patients with acromegaly were included, 61% were women, and 95% have macroadenomas. Previous treatments were surgery (89%), radiotherapy (34%), somatostatin analogs (99%), and/or cabergoline (67%). No patients were controlled at inclusion with high IGF1 (median 209% of ULN) and high GH secretion. For most patients the initial dose was 10 mg/day, and the median exposure was 30.5 months. Pegvisomant was used as monotherapy in 11%. IGF1 normalisation was obtained in 74% of patients with a median dose of 15 mg/day when used alone and 10 mg/day in combined therapy. In this study, there were three response predictors: exposure time, GH pretreatment, and IGF1 pretreatment (Table 1) [14].
\nIn a recent meta-analysis of eight studies, 60.9% of patients were controlled (52–70; 95% CI) and 72% if considering only patients in monotherapy in five studies [15].
\nInterestingly, there are two cases of persistent remission of acromegaly after pegvisomant withdrawal. Patients were treated for 8 and 11 years and presented a normal IGF1 and GH secretion 5 and 2 years after withdrawal, respectively [16].
\nIn a recent study, treatment adherence to pegvisomant was evaluated in a multicentre cross-sectional study on patients treated with pegvisomant for more than 12 months in 108 patients. Rates of adherence varied from 61 to 92% and did not correlate to disease control. Older patients and patients with an alternative schedule had lower adherence. However, treatment satisfaction was high, 75 ± 15%, evaluated with the “Treatment Satisfaction with Medicines Questionnaire” (STATMED-Q). This study reveals that the principal obstacle was the transportation of the pegvisomant (especially maintaining the cold chain during transportation) and anxiety about the injection. One third of patients made mistakes during the reconstitution (17%) and administration (22%) of pegvisomant [17].
\nExperience of pegvisomant in children is quite rare. There is a recent review of the case series of gigantism in the literature. Out of 262 patients, 42 (17.5%) were treated with pegvisomant and 27 (58%) had normal IGF1 [18]. The biggest series was published in 2015 with 208 patients with gigantism. Among them 37 were treated with pegvisomant and 19/37 (51%) had a normal IGF1. Indeed, gigantism seems to be more difficult to control than acromegaly in adulthood with pegvisomant [19].
\nEndocrine society guidelines for acromegaly were published in 2014 [20]. The first recommended treatment of acromegaly is surgery, as it offers the prospect of a cure. In case of persistent GH secretion 12 weeks after surgery, medical treatment is indicated including cabergoline and long-acting somatostatin (SMS) analogs. Cabergoline is indicated in case of co-secretion of GH and PRL or if GH secretion is slightly increased (IGF1 < 2.5 times the upper normal range) and permits 40–50% of control [21, 22]. The first generation of long-acting SMS analog studies report around 50% of IGF1 normalisation [23]. For patients who are not controlled by the first-generation SMS analogs, the recent consensus recommends several options:
Add cabergoline if IGF1 is <2.5 times the upper normal range.
Switch to pasireotide, the second-generation of SMS analogs which normalised IGF1 in up to 54% of patients [24].
Switch or add pegvisomant [25].
Pegvisomant is indicated in cases of resistance to SMS analog in a second- or third-line therapy [20]. In addition, pegvisomant should be considered in patient with uncontrolled diabetes with partial or no response to first-line medical therapy [25].
\nFor the first dose, 80 mg is recommended, followed by 10 mg/day. IGF1 should be measured 8 weeks after, and pegvisomant should be increased by stages of 5 mg.
\nThe dose of pegvisomant required to normalise IGF1 can be evaluated with age and BMI; however, it is recommended to monitor IGF1 in order to adapt pegvisomant dosage. Using dose above 30 mg/day is not recommended [26].
\nWhen patients are not controlled with somatostatin analog ± cabergoline, the question of adding pegvisomant or switching to pegvisomant is not yet resolved. Initially, with serum IGF1 normalisation in over 90% of patients with acromegaly receiving pegvisomant, the indications for combined therapy were limited. However, in real life, as efficacy is lower (almost 70%), the combination therapy is questionable. Moreover, because of the risk of tumour growth and chiasma compression, the strategy for macroadenoma was often to add pegvisomant to somatostatin analog. However, the routine use of SMS analog and pegvisomant in combination may also be prohibitively expensive [27].
\nA randomised trial compared the two strategies for patients uncontrolled under long-acting octreotide: switched to pegvisomant alone or added pegvisomant. IGF1 normalisation was similar in both groups (56% for pegvisomant alone and 62% for combined therapy). The question still remains unanswered [28].
\nIn a large Dutch cohort of patients with acromegaly treated with the association of somatostatin analog and pegvisomant for 9 years, 97% of patients had a normal IGF1 with a median dose of pegvisomant of 80 mg/week [29].
\nMoreover, the association of cabergoline and pegvisomant for patients with a slightly increase of IGF1 under pegvisomant alone for 18 months enabled acromegaly control in four patients (28%) [22].
\nIGF1 is the only biological marker to evaluate disease activity on pegvisomant. As it is a GH antagonist, it is not recommended to follow GH secretion. Indeed, scoring systems have been developed to evaluate the activity of acromegaly. In this way, SAGIT and ACRODAT are additional tools to assess overall disease activity [30, 31]. AcroQol can be useful to evaluate the quality of life of acromegaly patient under treatment [32].
\nIn the phase III study, one patient with 15 mg/day of pegvisomant withdrew after 8 weeks of therapy because of elevated serum aminotransferase levels, with a normalisation of liver function after withdrawal. In this patient, serum alanine aminotransferase and aspartate aminotransferase rose to 20 N and 10 N, respectively. In the cohort of patients receiving pegvisomant, mean serum aminotransferase levels were stable (n = 80) [11].
\nIn the Brazilian and Argentinian cohort, elevation of liver enzymes was reported in 9% of cases and was responsible for pegvisomant discontinuation in 1 and 5 patients, respectively (Table 1) [14, 33].
\nA recent meta-analysis of 6 studies with pegvisomant in monotherapy showed an overall rate of transaminase elevation of 3.0% (1.7–5.2%; 95% CI; I 2 = 55%) (Table 1) [15].
\nIn the phase III study, one patient with 15 mg/day of pegvisomant withdrew due to persistent headaches [11]. In the Brazilian real-life study, headaches were reported in two cases (1.8%) [14].
\nIn the phase III study, injection site reactions were reported in six patients (5%) receiving pegvisomant [11]. In the Brazilian real-life study, it was reported in 4.6% of patients [14]. Pain from injection was reported in 2.7% patients.
\nIn the Argentinian cohort, 3 out of 75 patients had localised lipodystrophy [33].
\nA recent meta-analysis of five studies with pegvisomant showed lipohypertrophy in 1.6% of patients (0.6–4.3%; 95% CI; I 2 = 69%) [15].
\nBecause of the nine amino acid substitutions, pegvisomant is different from GH and can be considered as foreign protein leading to an immunoreactivity. Pegylation of the molecule reduces immunogenicity. However, in the phase III study and its extension, anti-GH antibodies were reported in 8/112 (7%) patients between 1:14 and 1:64 and pegvisomant antibody in 16.9% [12, 15].
\nSeveral studies evaluated glucose metabolism in patients with pegvisomant. In 53 patients initially treated by long-acting octreotide, the switch for pegvisomant treatment induced normalisation of IGF1 in 78% of cases at 32 weeks and a significant diminution of median fasting glucose (1.4 mmol/l) and HbA1C (−0.2%) whatever the diabetes and IGF1 status. In the subgroup of diabetic patients, a significant decrease of HbA1C (−1%) was observed [34].
\nIn the ACROSTUDY, among the 1762 patients, 29% had diabetes before pegvisomant. At year 4, mean fasting blood glucose decreased from 140 ± 59 to 120 ± 44 mg/dl, and the decrease of HbA1C was not significant whatever the diabetes status [35].
\nIn a recent meta-analysis, pegvisomant significantly decreased fasting blood glucose level (−0.8 mmol/l; 95% CI; −1.0 to −0.6), fasting insulin level (−5.31; 95% CI; −10.2 to −0.4), and HbA1c (−0.43%; 95% CI; −0.6 to −0.3). Indeed, HOMA-I also decreased −0.61 (95% CI; −1.2 to −0.04). This increase in glucose metabolism was not correlated to IGF1 level [36].
\nIn the ACROSTUDY, subjects received pegvisomant for a mean of 5.4 years, and 12 out of 542 subjects (2.2%) had a confirmed increase in tumour size (Table 1) [37].
\nIn the Brazilian study, tumour enlargement was reported in 6.5% of cases (n = 5). In the Argentinian study, 4 of 50 patients (8%) showed an increase in tumour size with pegvisomant (Table 1) [33]. In the meta-analysis of five studies with pegvisomant in monotherapy, the overall tumour growth rate was 7.2% (4.8–10.7%; 95% CI; I 2 = 0%) [15].
\nThe bone is a well-known fragility key point in acromegaly with a high incidence of vertebral fractures [38]. A recent study evaluated vertebral fracture in 55 patients resistant to the first generation of somatostatin analogs. Before introducing pasireotide or pegvisomant, vertebral fracture occurred in 23 patients (42%). In uncontrolled acromegaly, there were 78% of vertebral fractures under pegvisomant and 25% under pasireotide (p = 0.04). In controlled acromegaly, there were 23% of vertebral fractures under pegvisomant and 12.5% under pasireotide (p = 0.4). Indeed, vertebral fractures seem to be more frequent with pegvisomant [39].
\nHowever, another longitudinal study has a different result in 83 patients treated with somatostatin analog alone (42 cases), pegvisomant alone (6 cases), or in combination with somatostatin analog (35 cases) for a median period of 82 months (range 36–126). In this longitudinal study, the authors observed a global decrease in incidence of radiological vertebral fractures from 43.9 to 26.8% (p = 0.039). For patients treated by pegvisomant, the incidence of vertebral fractures was not significantly decreased as compared to patients treated with somatostatin analog (10.0 vs. 26.7%; p = 0.09). In this study, pegvisomant did not increase vertebral fractures [40].
\nPegvisomant is an antagonist of GH receptor with a good efficacy. It can be used alone or in association with somatostatin analog or cabergoline if acromegaly is not controlled with somatostatin analog alone. The efficacy in real life is around 75% in acromegaly and 50% for gigantism. Indeed, pegvisomant can be used in the second medical stage after somatostatin analog.
\nAs an Open Access publisher, IntechOpen is dedicated to maintaining the highest ethical standards and principles in publishing. In addition, IntechOpen promotes the highest standards of integrity and ethical behavior in scientific research and peer-review. To maintain these principles IntechOpen has developed basic guidelines to facilitate the avoidance of Conflicts of Interest.
",metaTitle:"Conflicts of Interest Policy",metaDescription:"As an Open Access publisher, IntechOpen is dedicated to maintaining the highest ethical standards and principles in publishing. In addition, IntechOpen promotes the highest standards of integrity and ethical behavior in scientific research and peer-review.",metaKeywords:null,canonicalURL:"/page/conflicts-of-interest-policy",contentRaw:'[{"type":"htmlEditorComponent","content":"In each instance of a possible Conflict of Interest, IntechOpen aims to disclose the situation in as transparent a way as possible in order to allow readers to judge whether a particular potential Conflict of Interest has influenced the Work of any individual Author, Editor, or Reviewer. IntechOpen takes all possible Conflicts of Interest into account during the review process and ensures maximum transparency in implementing its policies.
\\n\\nA Conflict of Interest is a situation in which a person's professional judgment may be influenced by a range of factors, including financial gain, material interest, or some other personal or professional interest. For IntechOpen as a publisher, it is essential that all possible Conflicts of Interest are avoided. Each contributor, whether an Author, Editor, or Reviewer, who suspects they may have a Conflict of Interest, is obliged to declare that concern in order to make the publisher and the readership aware of any potential influence on the work being undertaken.
\\n\\nA Conflict of Interest can be identified at different phases of the publishing process.
\\n\\nIntechOpen requires:
\\n\\nCONFLICT OF INTEREST - AUTHOR
\\n\\nAll Authors are obliged to declare every existing or potential Conflict of Interest, including financial or personal factors, as well as any relationship which could influence their scientific work. Authors must declare Conflicts of Interest at the time of manuscript submission, although they may exceptionally do so at any point during manuscript review. For jointly prepared manuscripts, the corresponding Author is obliged to declare potential Conflicts of Interest of any other Authors who have contributed to the manuscript.
\\n\\nCONFLICT OF INTEREST – ACADEMIC EDITOR
\\n\\nEditors can also have Conflicts of Interest. Editors are expected to maintain the highest standards of conduct, which are outlined in our Best Practice Guidelines (templates for Best Practice Guidelines). Among other obligations, it is essential that Editors make transparent declarations of any possible Conflicts of Interest that they might have.
\\n\\nAvoidance Measures for Academic Editors of Conflicts of Interest:
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\\n\\nIf a manuscript is submitted by an Author who is a member of an Academic Editor's family or is personally or professionally related to the Academic Editor in any way, either as a friend, colleague, student or mentor, the work will be handled by a different Academic Editor who is not in any way connected to the Author.
\\n\\nCONFLICT OF INTEREST - REVIEWER
\\n\\nAll Reviewers are required to declare possible Conflicts of Interest at the beginning of the evaluation process. If a Reviewer feels he or she might have any material, financial or any other conflict of interest with regards to the manuscript being reviewed, he or she is required to declare such concern and, if necessary, request exclusion from any further involvement in the evaluation process. A Reviewer's potential Conflicts of Interest are declared in the review report and presented to the Academic Editor, who then assesses whether or not the declared potential or actual Conflicts of Interest had, or could be perceived to have had, any significant impact on the review itself.
\\n\\nEXAMPLES OF CONFLICTS OF INTEREST:
\\n\\nFINANCIAL AND MATERIAL
\\n\\nNON-FINANCIAL
\\n\\nAuthors are required to declare all potentially relevant non-financial, financial and material Conflicts of Interest that may have had an influence on their scientific work.
\\n\\nAcademic Editors and Reviewers are required to declare any non-financial, financial and material Conflicts of Interest that could influence their fair and balanced evaluation of manuscripts. If such conflict exists with regards to a submitted manuscript, Academic Editors and Reviewers should exclude themselves from handling it.
\\n\\nAll Authors, Academic Editors, and Reviewers are required to declare all possible financial and material Conflicts of Interest in the last five years, although it is advisable to declare less recent Conflicts of Interest as well.
\\n\\nEXAMPLES:
\\n\\nAuthors should declare if they were or they still are Academic Editors of the publications in which they wish to publish their work.
\\n\\nAuthors should declare if they are board members of an organization that could benefit financially or materially from the publication of their work.
\\n\\nAcademic Editors should declare if they were coauthors or they have worked on the research project with the Author who has submitted a manuscript.
\\n\\nAcademic Editors should declare if the Author of a submitted manuscript is affiliated with the same department, faculty, institute, or company as they are.
\\n\\nPolicy last updated: 2016-06-09
\\n"}]'},components:[{type:"htmlEditorComponent",content:"In each instance of a possible Conflict of Interest, IntechOpen aims to disclose the situation in as transparent a way as possible in order to allow readers to judge whether a particular potential Conflict of Interest has influenced the Work of any individual Author, Editor, or Reviewer. IntechOpen takes all possible Conflicts of Interest into account during the review process and ensures maximum transparency in implementing its policies.
\n\nA Conflict of Interest is a situation in which a person's professional judgment may be influenced by a range of factors, including financial gain, material interest, or some other personal or professional interest. For IntechOpen as a publisher, it is essential that all possible Conflicts of Interest are avoided. Each contributor, whether an Author, Editor, or Reviewer, who suspects they may have a Conflict of Interest, is obliged to declare that concern in order to make the publisher and the readership aware of any potential influence on the work being undertaken.
\n\nA Conflict of Interest can be identified at different phases of the publishing process.
\n\nIntechOpen requires:
\n\nCONFLICT OF INTEREST - AUTHOR
\n\nAll Authors are obliged to declare every existing or potential Conflict of Interest, including financial or personal factors, as well as any relationship which could influence their scientific work. Authors must declare Conflicts of Interest at the time of manuscript submission, although they may exceptionally do so at any point during manuscript review. For jointly prepared manuscripts, the corresponding Author is obliged to declare potential Conflicts of Interest of any other Authors who have contributed to the manuscript.
\n\nCONFLICT OF INTEREST – ACADEMIC EDITOR
\n\nEditors can also have Conflicts of Interest. Editors are expected to maintain the highest standards of conduct, which are outlined in our Best Practice Guidelines (templates for Best Practice Guidelines). Among other obligations, it is essential that Editors make transparent declarations of any possible Conflicts of Interest that they might have.
\n\nAvoidance Measures for Academic Editors of Conflicts of Interest:
\n\nFor manuscripts submitted by the Academic Editor (or a scientific advisor), an appropriate person will be appointed to handle and evaluate the manuscript. The appointed handling Editor's identity will not be disclosed to the Author in order to maintain impartiality and anonymity of the review.
\n\nIf a manuscript is submitted by an Author who is a member of an Academic Editor's family or is personally or professionally related to the Academic Editor in any way, either as a friend, colleague, student or mentor, the work will be handled by a different Academic Editor who is not in any way connected to the Author.
\n\nCONFLICT OF INTEREST - REVIEWER
\n\nAll Reviewers are required to declare possible Conflicts of Interest at the beginning of the evaluation process. If a Reviewer feels he or she might have any material, financial or any other conflict of interest with regards to the manuscript being reviewed, he or she is required to declare such concern and, if necessary, request exclusion from any further involvement in the evaluation process. A Reviewer's potential Conflicts of Interest are declared in the review report and presented to the Academic Editor, who then assesses whether or not the declared potential or actual Conflicts of Interest had, or could be perceived to have had, any significant impact on the review itself.
\n\nEXAMPLES OF CONFLICTS OF INTEREST:
\n\nFINANCIAL AND MATERIAL
\n\nNON-FINANCIAL
\n\nAuthors are required to declare all potentially relevant non-financial, financial and material Conflicts of Interest that may have had an influence on their scientific work.
\n\nAcademic Editors and Reviewers are required to declare any non-financial, financial and material Conflicts of Interest that could influence their fair and balanced evaluation of manuscripts. If such conflict exists with regards to a submitted manuscript, Academic Editors and Reviewers should exclude themselves from handling it.
\n\nAll Authors, Academic Editors, and Reviewers are required to declare all possible financial and material Conflicts of Interest in the last five years, although it is advisable to declare less recent Conflicts of Interest as well.
\n\nEXAMPLES:
\n\nAuthors should declare if they were or they still are Academic Editors of the publications in which they wish to publish their work.
\n\nAuthors should declare if they are board members of an organization that could benefit financially or materially from the publication of their work.
\n\nAcademic Editors should declare if they were coauthors or they have worked on the research project with the Author who has submitted a manuscript.
\n\nAcademic Editors should declare if the Author of a submitted manuscript is affiliated with the same department, faculty, institute, or company as they are.
\n\nPolicy last updated: 2016-06-09
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