Summary of the recommended quality parameters for peptides used as radiopharmaceutical precursors.
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Barely three months into the new year and we are happy to announce a monumental milestone reached - 150 million downloads.
\n\nThis achievement solidifies IntechOpen’s place as a pioneer in Open Access publishing and the home to some of the most relevant scientific research available through Open Access.
\n\nWe are so proud to have worked with so many bright minds throughout the years who have helped us spread knowledge through the power of Open Access and we look forward to continuing to support some of the greatest thinkers of our day.
\n\nThank you for making IntechOpen your place of learning, sharing, and discovery, and here’s to 150 million more!
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This concept of personalized medicine or theranostics can be traced back to the beginnings of nuclear medicine when radioisotopes were uncovered as diagnostic and therapeutic tools. Nowadays, the field of theranostics is in flux, as new techniques and materials allow a growing range of applications beneficial for patients. This book examines new developments in theranostics and provides a comprehensive overview of the state of the art in this exciting discipline.",isbn:"978-1-83962-788-0",printIsbn:"978-1-83962-783-5",pdfIsbn:"978-1-83962-789-7",doi:"10.5772/intechopen.91073",price:119,priceEur:129,priceUsd:155,slug:"theranostics-an-old-concept-in-new-clothing",numberOfPages:154,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"a283d1440c4b263c007d3f893f34c4f7",bookSignature:"Elisabeth Eppard",publishedDate:"September 29th 2021",coverURL:"https://cdn.intechopen.com/books/images_new/10232.jpg",numberOfDownloads:2015,numberOfWosCitations:0,numberOfCrossrefCitations:1,numberOfCrossrefCitationsByBook:0,numberOfDimensionsCitations:1,numberOfDimensionsCitationsByBook:0,hasAltmetrics:0,numberOfTotalCitations:2,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"June 17th 2020",dateEndSecondStepPublish:"September 11th 2020",dateEndThirdStepPublish:"November 10th 2020",dateEndFourthStepPublish:"January 29th 2021",dateEndFifthStepPublish:"March 30th 2021",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"245845",title:"Dr.",name:"Elisabeth",middleName:null,surname:"Eppard",slug:"elisabeth-eppard",fullName:"Elisabeth Eppard",profilePictureURL:"https://mts.intechopen.com/storage/users/245845/images/system/245845.png",biography:"Dr. Elisabeth Eppard is a radiochemist working on the development and process implementation of new compounds for theranostic application. In 2013 she obtained her Ph.D. under Prof. Rösch at the Institute of Nuclear Chemistry, Johannes Gutenberg University Mainz, Germany, where she worked on radiometal-based radiopharmaceuticals. After four years as a junior research group leader in the Department of Nuclear Medicine, University Hospital Bonn, Germany, Dr. Eppard joined Positronpharma SA, Santiago, Chile, as a senior scientist in 2018. There she was responsible for research and clinical applications based on 68Ga-, 44Sc-, and 177Lu-labelled theranostics. Since 2021, she has been a radiochemist in the Department of Nuclear Medicine, University Hospital Magdeburg, Germany, where she is continuing her research.",institutionString:"University Hospital Magdeburg",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"University Hospital Magdeburg",institutionURL:null,country:{name:"Germany"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"1202",title:"Pharmacotherapy",slug:"pharmacology-toxicology-and-pharmaceutical-science-pharmacology-pharmacotherapy"}],chapters:[{id:"74628",title:"Radiopharmaceutical Precursors for Theranostics",doi:"10.5772/intechopen.95438",slug:"radiopharmaceutical-precursors-for-theranostics",totalDownloads:378,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Due to the complex nomenclature used in various regulations and guidance documents, the understanding of radiopharmaceutical precursor’s definition might be challenging. Depending on the context it could be interpreted as the substance which becomes a radiopharmaceutical after radiolabeling with a radionuclide of choice or a radionuclide which is used for radiolabeling of that substance. In this Chapter we present and discuss the requirements for precursors which are used in the preparation of theranostic radiopharmaceuticals, in particular for preparation of new radiopharmaceuticals for clinical trials within the EU. In discussion on the available methods for assessing the quality of radiopharmaceutical precursors and on the specified limits the reference to Ph. Eur. is made. Since the EANM guidelines for in-house preparation of radiopharmaceuticals also specify the need for testing the quality of radiopharmaceutical precursors, information provided herein might help the radiopharmacist working on the development of new theranostic agents to adequately define identity, strength, quality, purity and stability of the final radiopharmaceutical preparation.",signatures:"Justyna Pijarowska-Kruszyna, Piotr Garnuszek, Clemens Decristoforo and Renata Mikołajczak",downloadPdfUrl:"/chapter/pdf-download/74628",previewPdfUrl:"/chapter/pdf-preview/74628",authors:[{id:"326467",title:"Associate Prof.",name:"Renata",surname:"Mikolajczak",slug:"renata-mikolajczak",fullName:"Renata Mikolajczak"},{id:"326470",title:"Dr.",name:"Justyna",surname:"Pijarowska-Kruszyna",slug:"justyna-pijarowska-kruszyna",fullName:"Justyna Pijarowska-Kruszyna"},{id:"339867",title:"Prof.",name:"Piotr",surname:"Garnuszek",slug:"piotr-garnuszek",fullName:"Piotr Garnuszek"},{id:"339868",title:"Prof.",name:"Clemens",surname:"Decristoforo",slug:"clemens-decristoforo",fullName:"Clemens Decristoforo"}],corrections:null},{id:"74944",title:"Pretargeted Theranostics",doi:"10.5772/intechopen.95567",slug:"pretargeted-theranostics",totalDownloads:257,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Personalized medicine is becoming an integral part of our healthcare system, in which theranostics play a fundamental role. Nanomedicines such as monoclonal antibodies are a commonly used targeting vector in such approaches due to their outstanding targeting abilities as well as their capabilities to function as drug delivery vehicles. However, the application of nanomedicines in a clinical setting is connected with several challenges. For example, nanomedicines typically possess slow pharmacokinetics in respect to target accumulation and excretion. For targeted radionuclide therapy, this results in high radiation burden to healthy tissue. For drug delivery systems, long circulation and excretion times of the nanomedicine complicate site-specific release approaches and limit as such the usability of these strategies. One way to circumvent these challenges is the use of pretargeting strategies, which allow to separate the accumulation and excretion of nanomedicines from the actual diagnostic or therapeutic application. As such, pretargeting allows to use theranostic concepts utilizing the same nanomedicine and determine the success chances with diagnostic measures before initiating therapy. This chapter will explain the concept of pretargeted theranostics, which pretargeting systems have thus far been developed and compare how these systems performed.",signatures:"Markus Staudt, Matthias M. Herth and Christian B.M. Poulie",downloadPdfUrl:"/chapter/pdf-download/74944",previewPdfUrl:"/chapter/pdf-preview/74944",authors:[{id:"328435",title:"Associate Prof.",name:"Matthias M.",surname:"Herth",slug:"matthias-m.-herth",fullName:"Matthias M. 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They rival the monoclonal antibodies and other specific biological ligands with respect to affinity, stability, robustness, non-immunogenicity and facile to synthesis. Nucleic acid aptamers are selected from an oligonucleotide library by an iterative process called SELEX (Systematic Evolution of Ligands by Exponential Enrichment Analysis). These aptamers are compatible to any kind of chemical modification, conjugation and functionalization. Briefly, this chapter discusses about the diagnostic and therapeutic application of aptamers.",signatures:"Arghya Sett",downloadPdfUrl:"/chapter/pdf-download/74614",previewPdfUrl:"/chapter/pdf-preview/74614",authors:[{id:"301899",title:"Dr.",name:"Arghya",surname:"Sett",slug:"arghya-sett",fullName:"Arghya Sett"}],corrections:null},{id:"74008",title:"Extracellular Vesicles: “Stealth Transport Aircrafts” for Drugs",doi:"10.5772/intechopen.94502",slug:"extracellular-vesicles-stealth-transport-aircrafts-for-drugs",totalDownloads:338,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:0,abstract:"Extracellular vesicles (EVs) can deliver many types of drugs with their natural source material transport properties, inherent long-term blood circulation capabilities and excellent biocompatibility, and have great potential in the field of drug carrier. Modification of the content and surface of EVs according to the purpose of treatment has become a research focus to improve the drug load and the targeting of EVs. EVs can maximize the stability of the drugs, prevent immune clearance and achieve accurate delivery. Therefore, EVs can be described as “stealth transport aircrafts” for drugs. This chapter will respectively introduce the application of natural EVs as cell substitutes in cell therapy and engineered EVs as carriers of nucleic acids, proteins, small molecule drugs and therapeutic viral particles in disease treatment. It will also explain the drug loading and modification strategies of EVs, the source and characteristics of EVs. In addition, the commercialization progress of EVs drugs will be mentioned here, and the problems in their applications will be discussed in conjunction with the application of EVs in the treatment of COVID-19.",signatures:"Chunying Liu, Xuejing Lin and Changqing Su",downloadPdfUrl:"/chapter/pdf-download/74008",previewPdfUrl:"/chapter/pdf-preview/74008",authors:[{id:"36101",title:"Dr.",name:"Changqing",surname:"Su",slug:"changqing-su",fullName:"Changqing Su"},{id:"326640",title:"Associate Prof.",name:"Chunying",surname:"Liu",slug:"chunying-liu",fullName:"Chunying Liu"},{id:"329915",title:"Ms.",name:"Xuejing",surname:"Lin",slug:"xuejing-lin",fullName:"Xuejing Lin"}],corrections:null},{id:"76288",title:"Graphene-Based Nanosystems: Versatile Nanotools for Theranostics and Bioremediation",doi:"10.5772/intechopen.96337",slug:"graphene-based-nanosystems-versatile-nanotools-for-theranostics-and-bioremediation",totalDownloads:260,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Since its revolutionary discovery in 2004, graphene— a two-dimensional (2D) nanomaterial consisting of single-layer carbon atoms packed in a honeycomb lattice— was thoroughly discussed for a broad variety of applications including quantum physics, nanoelectronics, energy efficiency, and catalysis. Graphene and graphene-based nanomaterials (GBNs) have also captivated the interest of researchers for innovative biomedical applications since the first publication on the use of graphene as a nanocarrier for the delivery of anticancer drugs in 2008. Today, GBNs have evolved into hybrid combinations of graphene and other elements (e.g., drugs or other bioactive compounds, polymers, lipids, and nanoparticles). In the context of developing theranostic (therapeutic + diagnostic) tools, which combine multiple therapies with imaging strategies to track the distribution of therapeutic agents in the body, the multipurpose character of the GBNs hybrid systems has been further explored. Because each therapy and imaging strategy has inherent advantages and disadvantages, a mixture of complementary strategies is interesting as it will result in a synergistic theranostic effect. The flexibility of GBNs cannot be limited to their biomedical applications and, these nanosystems emerge as a viable choice for an indirect effect on health by their future use as environmental cleaners. Indeed, GBNs can be used in bioremediation approaches alone or combined with other techniques such as phytoremediation. In summary, without ignoring the difficulties that GBNs still present before being deemed translatable to clinical and environmental applications, the purpose of this chapter is to provide an overview of the remarkable potential of GBNs on health by presenting examples of their versatility as nanotools for theranostics and bioremediation.",signatures:"Marlene Lúcio, Eduarda Fernandes, Hugo Gonçalves, Sofia Machado, Andreia C. Gomes and Maria Elisabete C.D. Real Oliveira",downloadPdfUrl:"/chapter/pdf-download/76288",previewPdfUrl:"/chapter/pdf-preview/76288",authors:[{id:"146462",title:"Prof.",name:"Maria Elisabete",surname:"C.D. 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This chapter deals with regulatory considerations related to radiopharmaceutical precursors within Europe. Outside, different aspects may apply, with the exception of certain harmonized documents. Radiopharmaceuticals are considered a safe class of medicinal products. Due to the small chemical quantities administered they are not expected to exhibit any measurable pharmacological effect [1]. However, since they are radioactive, the rules for minimizing the risk associated with the use of ionizing radiation to the patients and to the personnel must be observed. Depending on the chemical and physical properties, radiopharmaceuticals are used in major clinical areas for diagnostics and/or therapy [2]. As defined by the European Pharmacopeia (Ph. Eur.) general monograph (0125)
Radiopharmaceutical precursors according to Ph. Eur.
Given the complex nomenclature used in various regulations and guidance documents, the understanding of radiopharmaceutical precursor’s definition might be challenging. Depending on the context it could be interpreted as the substance which becomes a radiopharmaceutical after radiolabeling with a radionuclide of choice or a radionuclide which is used for radiolabeling of that substance. Therefore, the quality requirements and test methods specifications of precursors for use in preparation of theranostic radiopharmaceuticals can be discussed only in the light of current regulatory framework.
The preparation and use of radiopharmaceuticals are regulated by number of directives, regulations and rules. These documents may be classified with respect to the status of radiopharmaceutical preparation:
radiopharmaceuticals with marketing authorization (MA), regulated by:
radiopharmaceuticals to be used in clinical trials (CT), regulated by:
unlicensed radiopharmaceuticals extemporaneously (just before use) prepared, not for CT [12, 13].
Radiopharmaceuticals with marketing authorization (MA) meet the requirements of GMP Annex 3 (Manufacture of Radiopharmaceuticals) [8] and EMA Guideline on Radiopharmaceuticals [12]. For the small scale preparation of radiopharmaceuticals outside the marketing authorization the guide of the Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme (PIC/S) [14], the Guidelines on Good Radiopharmacy Practice (CRPP) issued by the Radiopharmacy Committee of European Association of Nuclear Medicine (EANM) [13] and the Chapter 5.19. Extemporaneous preparation of radiopharmaceutical preparations of the Ph. Eur. [15] are setting standards for good practices.
The translation of new radiopharmaceuticals from the preclinical stage into clinical trials requires appropriate quality assessment essential to ensure efficacy and safety of both drug substance and drug product [16, 17]. The specific regulatory framework for the use of radiopharmaceuticals in clinical trials has been established in Europe [9, 11, 18]. From the radiopharmaceutical development perspective, the essential step is the preparation of an Investigational Medicinal Product Dossier (IMPD). This document includes information related to the chemical and pharmaceutical quality of the drug substance and drug product, as well as non-clinical data related to pharmacology, pharmacokinetics, radiation dosimetry and toxicology [19]. IMPD contains two main sections related to the production and quality control of the radiopharmaceutical: the drug substance (the active pharmaceutical ingredient, or API) and the drug product.
An
The manufacture of APIs should be carried out following general GMP requirements. In a GMP-based system, all processes are defined, systematically reviewed, and shown to be capable of consistently providing medicinal products of the required quality and complying with their specifications [20]. Written and approved protocols specifying critical steps, acceptance criteria, must be in place. Process validation is a crucial part of GMP, meaning that all critical steps of manufacturing processes as well as significant changes to these processes are validated. It should be noted that the requirements for validations differ depending whether marketing authorization, clinical trials or in-house preparation of radiopharmaceuticals are planned (see also Figure 2.) [21]. The qualification and validation aspects related to the small-scale “in house” preparation of radiopharmaceuticals are covered in the EANM guidance [22].
Requirements for chemical precursors used in preparation of radiopharmaceuticals depending on their regulatory status.
In the process of IMPD preparation the prime challenge is to establish quality specifications for radiopharmaceutical precursors. They are supposed to comprise a set of tests that are necessary to confirm identity, purity and strength of the drug substance. Issues under consideration are the definition of release criteria, analytical procedures and especially their validation. Main references to address these issues are the European Pharmacopeia and guidance provided by the International Conference on Harmonization (ICH). Ph. Eur. provides general requirements for quality control of radiopharmaceutical precursors, in addition, a number of monographs for individual radiopharmaceuticals and chemical precursors are available in the Ph. Eur.
The use of analytical methods described in the pharmacopeia allows to reduce the work load related to analytical method validation. This does not mean that a pharmacopeia method may be implemented without any preliminary testing and verification. As a minimum, the most critical parameters should be verified, depending on the intended method. If no pharmacopeia monograph exists, analytical methods need to be fully validated. As stated by the general reference document issued by ICH the objective of validation of an analytical procedure is to demonstrate that it is suitable for its intended purpose [23]. To validate an analytical method, the following characteristics may be considered: specificity, accuracy, linearity range, precision (repeatability and intermediate precision), limit of detection (LOD), limit of quantitation (LOQ) and robustness. Recently, recommendations for the validation of analytical methods which are specific for radiopharmaceuticals has been published by EANM [24].
Chemical precursors for radiopharmaceutical preparations, are non-radioactive substances obtained by chemical synthesis for combination with a radionuclide in contrast to precursors manufactured using substances of human or animal origin [4].
The quality specification for chemical precursors is built upon three elements: exact methods, test limits and selection of reference standard. Pharmacopeia monographs comprise a set of critical attributes categorized into three subdivisions: identity, tests (related substances, residual solvents, metal catalyst or metal reagent residues, microbial contamination, bacterial endotoxin) and assay of the active substance. To ensure the appropriate quality, reference substances (like primary standards e.g. Ph. Eur. Chemical Reference Substance, CRS, or Pharmaceutical Secondary Standard, PSS) are used as a standard in an assay, identifications, or purity test. CRS or PSS are often characterized and evaluated for its intended purpose by additional procedures other than those used in routine testing [25].
For in-house prepared radiopharmaceuticals the confirmation of the chemical identity and purity of the precursor are the minimum quality control required, in order to qualify the material for subsequent clinical radiolabeling. Additional testing may apply if necessary for the specific process. For example, testing of trace metals content may not be necessary when the material will be subsequently radiolabeled with halogens, but is absolutely critical when the material is intended for labelling with radiometals [26].
To bring a novel radiopharmaceutical into the clinic it is needed that specific quality requirements for the radiopharmaceutical precursor are established, the range of testing would depend on their status and/or intended use. It is worth noting that for Phase I clinical trials full analytical validation is not necessary (only method suitability should be confirmed) [21]. While analytical methods used to evaluate a batch of API for clinical trials may not yet be validated, they should be scientifically sound [27].
There are some specific requirements for the large-sized molecules (e.g. proteins or monoclonal antibodies) as radiopharmaceutical precursors [28]. Monoclonal antibodies are immunoglobulins (Ig) with a defined specificity derived from a monoclonal cell line. Their biological activities are characterized by a specific binding characteristic to a target ligand (e.g. antigen) and they may be generated by recombinant DNA (rDNA) technology, hybridoma technology, B lymphocyte immortalization or other technologies. Generally, when chemical precursors are manufactured using substances of human or animal origin, the requirements of Ph. Eur. chapter 5.1.7. Viral safety [29] and the general monograph Products with risk of transmitting agents of animal spongiform encephalopathies (1483) [30] apply.
Stability testing is part of the chemical precursor’s characterization. Detailed requirements for carrying out stability studies are included in the ICH guideline Q1A (R2) [31]. The purpose of stability testing is to provide evidence on how the quality of a substance varies with time under the influence of a variety of environmental factors such as temperature, humidity, and light, and to establish a re-test period and recommended storage conditions. Stability studies should be carried out on at least three batches and include testing parameters of the chemical precursor that are susceptible to changes during storage and may affect quality, safety and efficacy (e.g. chemical purity and/or assay). The validated analytical methods should be used in these tests. For method validation, it is essential to investigate degradation products and establish degradation pathways under stress conditions (e.g. heat, humidity, light, acid/base hydrolysis and oxidation).
Peptides are an emerging class of compounds that have application in theranostics of several diseases, mainly in cancer [32, 33, 34, 35, 36]. These chemical precursors are positioned between the classic small organic molecules and the high molecular weight biomolecules. The interest of the scientific community for peptide drugs has been continuously growing. Currently, more than 60 peptide-based pharmaceuticals are marketed, over 150 peptides are in active clinical trials and estimated 500 more are in preclinical stages of development [37, 38]. Chemically, peptides have poly-amino acids structure ranging from 3 to 100 amino acids (less than 10 kDa) linked by a peptide (amide, –CONH–) bond, and are lacking a tertiary structure. From the biological point of view, peptides are important regulators of growth and cellular functions in normal tissue and tumors. They can act as cytokines, chemokines, neurotransmitters, hormones and growth factors. Generally, they offer many advantages over other groups for radiopharmaceutical applications. Peptides demonstrate high receptor specificity and selectivity, as well as binding affinity, good tissue penetration and favorable pharmacokinetic profiles. Most of them is characterized by low toxicity and immunogenicity [39, 40]. Their compact size results in rapid targeting and blood clearance. As a consequence low nonspecific uptake in non-targeted tissues and high target-to-background ratios are achieved. Moreover, peptides can be easily chemically synthesized in high purity, modified and stabilized to obtain optimized pharmacokinetic parameters. These all attributes together with ability to attach different chelating agents, prosthetic group and availability of various bioconjugation techniques make peptides an important target platform for theranostic radiopharmaceuticals [41, 42].
Peptide-based radiopharmaceuticals were introduced into the clinic more than three decades ago [43]. Since that time, several theranostic radioligand platforms are used for diagnosis and peptide receptor radionuclide therapy (PRRT) of different cancer types. In this concept, peptide analogs directed against somatostatin receptors (SSTR) play a crucial role [44]. The most prominent example of the theranostic pair of radiolabeled peptides are DOTA-conjugated SSTR agonist DOTA-(D-Phe1, Tyr3, Thr8)-octreotate (DOTA-TATE) labeled with 68Ga and 177Lu (Figure 3). The marketing authorization of NETSPOT® ([68Ga]Ga-DOTATATE) in 2016 and LUTATHERA® ([177Lu]Lu-DOTATATE) in early 2018 [45] encouraged the research in this field to develop improved radiolabeled peptides targeting other receptor/antigen families, exemplified by the prostate specific membrane antigen (PSMA) [46], gastrin-releasing peptide receptor (GRPr) [47] and cholecystokinin-2 receptor (CCK2R) [48, 49]. Some of these peptides are currently under clinical investigation.
Structure of DOTA-TATE for labelling with theranostics pair of radionuclides: Gallium-68 (68Ga) and lutetium-177 (177Lu).
Peptides as precursors for radiopharmaceutical preparations, similarly to other chemical precursors, require adequate specification as a part of their quality assurance in order to demonstrate the safety and efficacy of the final radiopharmaceutical preparation. Currently, no individual pharmacopeia monograph of peptide used as radiopharmaceutical precursors is available. Thus, the quality specification should be established according to the general requirements [4, 50]. Herein, we provide an overview of recommended methods and test limits for the characterization of peptides. The set of analytical procedures that need to be considered is presented in Table 1. However, it should be noted that new analytical methods and modifications to existing ones are continuously being developed and should be utilized where appropriate.
Parameters | Typical methods | Typical acceptance criteria |
---|---|---|
- Appearance/color | Visual inspection | White or almost white powder |
- Solubility | Visual inspection | Solubility in water, ethanol and dilute acid or alkali |
- Active moiety | RP-HPLC-UV | Retention time |
MS or | Mass spectrum | |
NMR | NMR spectrum | |
IR | IR spectrum | |
AAA (GC) | AA: theoretical content ±20% | |
- Related substances | HPLC-UV | Individual, unidentified: < 2.0% Total: ≤ 3.0% |
- Residual solvents | (Headspace) GC | Acetonitrile: ≤ 0.5% |
- Residual metals | AAS/ICP-AES/ICP-MS | Pt, Pd, Ir, Rh, Ru, Os, Mo, Ni, Cr, V, Pb, Hg, Cd, Tl: ≤ 0.01% |
- Residual reagents | HPLC-UV/IC/GC | Trifluoracetic acid: ≤ 1.0%* |
HPLC-UV/IC/GC | Acetic acid: target ±5% Trifluoracetic acid: target ±5% | |
Karl-Fisher | ≤ 10.0% | |
RP-HPLC-UV or CHN | ≥ 75.0% | |
TAMC plate count | ≤ 103 CFU/g for bulk ≤ 102 CFU per container | |
TYMC plate count | ≤ 102 CFU/g for bulk ≤ 101 CFU per container | |
Gel-clot | ≤ 100 IU/g for bulk ≤ 10 IU per container |
Summary of the recommended quality parameters for peptides used as radiopharmaceutical precursors.
The residual TFA content is determined when AcOH or HCl are used as counter-ions.
The preliminary quality evaluation of peptides is based on the visual inspection of the appearance/color and solubility. This parameter is given only for information, it is not a requirement in a strict sense. If any of the characteristics change during storage, this change should be investigated and appropriate action taken. A typical description of peptide appearance is: white to almost white, freeze-dried powder and solubility is stated in water, ethanol and dilute solutions of acids and alkali [38, 51].
According to the ICH Q6A guideline [25] identification testing should allow to discriminate between compounds of closely related structure which are likely to be present (e.g. peptides with altered sequences or functional groups that may be formed during the synthesis). The identification test should include combination of different procedures (mostly two) and should be specific and unequivocal. Several techniques are currently in use for confirmation of peptide identity: HPLC-UV, nuclear magnetic resonance spectrometry (NMR), mass spectrometry (MS), infrared absorption spectrophotometry (IR), amino acid analysis (AAA) or peptide sequencing [51]. The method of choice is typically HPLC-UV based on retention time by comparison with reference standard, since the separation by RP-HPLC is often utilized and the method is widely available. UV detection of peptides is realized at 210–220 nm and 250–290 nm for aromatic side chains of phenylalanine, tyrosine and tryptophan. Identification solely by a chromatographic retention time is not regarded as specific and should be complemented by spectrometric techniques. The NMR spectroscopy is the method that allows to unequivocally define the structure of a peptide in the terms of amino acid composition, sequence and chirality. Identification by NMR spectrometry is usually limited to peptides comprising up to 15 amino acids and requires complex data interpretation. For this reason NMR technique is primarily replaced by mass spectroscopy (MS). This technique provides highly accurate molecular weight information on intact molecules, which is an advantage of MS for peptide identification. The peptide molecular mass is most commonly determined by using the electrospray ionization method (ESI), which occurs through the addition or removal of protons and appears as singly or doubly charged ions. As alternative for the more sophisticated spectroscopic methods, amino acid analysis (AAA) could be considered. This technique involves the hydrolysis of the peptide (usually in acidic conditions) to its individual amino acid residues, followed by chromatographic separation and detection/quantification. The method also enables the determination of the enantiomeric purity with the use of appropriate reference standards. However, this method may not be applicable to peptides containing unnatural amino acids and/or specific chelators. The NMR and AAA as well as peptide sequencing techniques are generally used for characterization of PSS.
In the two recently published papers the identity of DOTA-TATE has been confirmed using suitable instrumental techniques; Sikora et al. [52] confirmed the identity of DOTA-TATE using three different methods: MS, IR and HPLC. Similarly, in the work by Raheem at al [53] the final product was analyzed using high resolution mass spectrometry for identification and analytical HPLC for purification; it was detected via analytical HPLC at a retention time of 9.52 min and detected by HRMS-ESI (calc m/z for [(DOTA-TATE +2H)/2]+: 718.3028, found: 718.3046 with −0.1144 ppm error).
In our experience ESI-MS in positive ionization mode was used to confirmed whether the masses of ions at m/z 1435.6 ± 1.0 [M + H]+ and 718.3 ± 1.0 [M + 2H]2+correspond to the monoisotopic mass of peptide [M] as presented in Figure 4. DOTA-TATE PSS was used as reference in IR analysis. Also a gradient HPLC-UV (220 nm) served as identity test of DOTA-TATE by comparison with the reference standard (Rt ± 5.0%). The same HPLC method was used for determination of peptide purity and assay. The representative HPLC chromatograms of DOTA-TATE and DOTA-TATE PSS are given in Figure 5.
ESI-MS spectrum for DOTA-TATE.
HPLC-UV (220 nm) chromatograms of (I) DOTA-TATE Rt = 19.831 min and (II) DOTA-TATE PSS Rt = 19,936 min. HPLC method: Luna C18(2) column; Mobile phase - A: water with 0.1% TFA, B: Acetonitrile with 0.1% TFA; gradient profile – From 0 to 25 min: 0–50% B; flow - 0.8 mL/min, oven temperature - 30°C.
Peptides are usually chemically synthesized using solid-phase peptide synthesis (SPPS) [54]. In this multi-stage process, amino acids are linked to each other during individual coupling steps, thus constructing the desired peptide sequence. This occurs when the carboxylic end of the sequence is covalently attached to a solid support matrix. The complexity of the peptide production process results in a greater diversity of potential impurities. Heterogenicity of the impurity profile is observed even among peptides manufactured by the same synthetic route. The impurities can originate from raw materials, the manufacturing process, degradation or may be formed during storage. Although protecting groups, scavengers or activated functional groups are used to prevent undesired side-chain reactions the peptide manufacturing process leads to formation of closely related impurities. The most common impurities are products of racemization, deamidation, amino acid deletion or insertion, acetylation, oxidation, β-elimination, cyclization, reduction and incomplete deprotection [51]. The presence of related peptide impurities is typically determined using gradient reversed-phase HPLC method with UV detection, because of its selectivity, high sensitivity, low limit of detection, quantification and robustness. The developed HPLC method should allow sufficient separation of potential impurities from manufacturing process as well as degradation products. The acceptance criteria for related substances according to the Ph. Eur. General Monograph 2902 [4] are presented in Table 2.
Specific thresholds should be applied for impurities known to be unusually potent or to produce toxic or unacceptable pharmacological effects.
The presence of inorganic impurity should also be considered, in particular when radiolabeling of the peptide with radiometals is concerned. According to the Ph. Eur. general monograph (2902), the metal residues in peptides should be determined if the manufacturing process is known or suspected to lead to its presence, e.g. due to the use of specific metal catalyst (e.g. Pd) or metal containing reagents. The content for each of the following metals: Pt, Pd, Ir, Rh, Ru, Os, Mo, Ni, Cr, V, Pb, Hg, Cd, Tl in the peptide precursors are limited to 0.01%. The metal impurities are typically examined using atomic absorption spectrometry (AAS), inductively coupled plasma with atomic emission spectrometry detection (ICP-AES) or mass spectrometry detection (ICP-MS) techniques. Determination of residual metals in peptides can be crucial for precursors intended for radiometal labeling [55]. It has been proven that the presence of certain metals can significantly affect the labeling efficiency through competitive chelation.
In addition to related substances the residual solvents are required to be examined as impurities in peptide precursors. Residual solvents in pharmaceuticals are defined as organic volatile chemicals that are used in the manufacturing process. The solvents are not completely removed by practical manufacturing techniques (e.g. lyophilization process). General guidelines established by the ICH divide solvents into three classes [56]. The Class 1 solvents should not be used in the final step of the manufacturing process of chemical precursors, because of toxicity and environmental impact. The use of the Class 2 solvents should be limited due to potential toxicity and Class 3 solvents are regarded as posing a lower risk to human health. Based on the permitted daily exposure (PDE), Class 2 and 3 solvents are limited to 0.5%. Residual solvents are typically determined using chromatographic techniques such as gas chromatography (GC) coupled with static headspace sampling. Many solvents are usually used in the peptides synthetic process. However, as the advantage of the SPPS and lyophilization process, the most frequently detected solvent is only acetonitrile (Class 2 solvent), used as the component of the mobile phase in the final purification process by preparative HPLC.
Synthetic peptides usually contain counter-ions on protonated amino functional groups (N-terminus, Arg, His, Lys, etc.). The presence of counter-ions such as acetate, chloride or trifluoroacetate results from the peptide post synthetic cleavage and/or purification process. Depending on the peptide sequence they reduce the net peptide content by 5 to 25%, but are not considered as impurity. Radiopharmaceutical preparations for diagnostic or therapeutic purposes are based on the net peptide content and thus the amount of residual counter-ions needs to be assessed. To determine counter-ion amounts different method are being used such as: GC, HPLC-UV or ion chromatography (IC). Trifluoroacetic acid (TFA) determined by IC at the level of ca. 20% in DOTA-TATE [52], corresponded to three TFA molecules associated to single peptide molecule. TFA is commonly used as a chemical reagent to remove residual protecting groups during purification of peptides and also as a mobile-phase modifier in a reversed-phase chromatography. Therefore, when the counter-ion finally is AcOH or HCl, determination of the TFA residual content is mandatory.
In order demonstrate a lot-to-lot consistency the test for water content (residual moisture remaining from the lyophilization process) should be also performed. This parameter may affect the stability of the peptide. For residual water Karl-Fischer titration method as well as GC method with thermal conductivity detector (TCD) [57] are commonly used and water content is limited to max. 10%.
Generally, assay is defined as a net peptide content. The lyophilized peptide contains also water, counter ions and residual solvents. The net peptide content is referred to percentage of peptide material in the lyophilized peptide. According to ICH guideline Q6A, a specific stability-indicating procedure should be included in the specifications to determine the content of the drug substance. There are two main approaches to determine net peptide content. The first method is a relative assay against a well-defined chemical reference substance, performed using comparative chromatographic procedures. Usually the same RP-HPLC method is used for both assay, identification and related substances. The second approach is an absolute assays involving a functional group (e.g. AAA or titration methods) or a nitrogen content analysis. The nitrogen content is determined from the results of elemental analysis CHN. The calculation of the net peptide content is based on the relation between determined %N to the theoretical content in the peptide structure. For example, this method was used to DOTA-TATE assay determination. Peptide content calculated from elemental analysis was ca. 78.0%, which was in agreement with the generally accepted limit ≥75% [52].
The presence of microorganisms may affect the stability of drug substances due to their propensity to degrade/metabolize peptides. Microbiological examinations involve the bioburden control (Ph. Eur 2.6.12) and content of bacterial endotoxins (Ph Eur. 2.6.14). The microbial enumeration tests for total aerobic microbial counts (TAMC) and total yeast and mold counts (TYMC) must adhere to the acceptance criteria of 103 CFU/g and 102 CFU/g for bulk material and 102 CFU/g and 101 CFU per container for chemical precursors packed in single and multi-dose containers, respectively. Bacterial endotoxin can be determined by the gel-clot or photometric methods (turbidimetric and chromogenic techniques) and acceptance criteria are limited to a maximum 100 IU/g for bulk material or maximum 10 IU per container for chemical precursors packed in single-dose and multidose containers.
Radionuclide precursors are offered as solutions for radiolabeling with MA, they are also locally produced for the in-house preparation of radiopharmaceuticals. There is an ongoing debate whether radionuclide precursors always have to be considered as medicinal product, or also can be provided as a starting material [58]. Unlike for chemical precursors for radiopharmaceutical preparation, up to date there is no monograph in the Ph. Eur. that sets out general requirements for radionuclide precursors. This is due to the fact that the quality requirements for radionuclides used to obtain diagnostic and therapeutic preparations are highly varying and depend on the irradiation route and chemical processing involved, which mainly affect the parameters of radionuclide purity or specific activity.
However, there are several individual Ph. Eur. monographs for radionuclide precursors. Two of these concern radionuclide precursors used to prepare radiopharmaceuticals for therapeutic use. These are:
Focusing attention on theranostic radiopharmaceuticals, herein the quality requirements only for metallic radionuclide precursors used in diagnostics and therapy are compared. Table 3 shows the exemplary quality requirements for radionuclide precursor for therapeutic use (177Lu) and a matching radionuclide precursor for diagnostic use (68Ga).
Reporting threshold | 0.2 per cent |
Identification threshold | 2.0 per cent |
Total unspecified impurities | Maximum 3.0 per cent |
Acceptance criteria for related substances [4].
Lutetium (177Lu) solution for radiolabelling (Ph. Eur. 2798 [59]) | Gallium (68Ga) chloride solution for radiolabelling (Ph. Eur. 2464 [60]) |
---|---|
RADIONUCLIDIC PURITY Gamma-ray spectrometry. - the total radioactivity due to ytterbium-175 (impurity B) is not more than 0.1 per cent; – the total radioactivity due to lutetium-177 m (impurity A) is not more than 0.07 per cent; – the total radioactivity due to radionuclidic impurities other than A and B is not more than 0.01 per cent. | RADIONUCLIDIC PURITY A. Gamma-ray spectrometry. B. Germanium-68 and gamma-ray-emitting impurities. Gamma-ray spectrometry. |
RADIOCHEMICAL PURITY | RADIOCHEMICAL PURITY |
Comparison of Ph. Eur. requirements for selected radionuclide precursors.
Comparing the requirements of these two monographs there are apparently large differences in numerical values seen, especially for metal ion content and radiochemical purity. However, when the radioactivity of these radionuclides (different for therapeutic or diagnostic use) is considered, there are basically no differences in quality requirements for both radionuclides. This can be demonstrated on the example of the DOTA-TATE preparations with 177Lu and 68Ga. For therapy 7.4 GBq of [177Lu]Lu-DOTA-TATE is used and this preparation contains ca. 0.2 mg of DOTA-TATE. Typical dose of [68Ga]Ga-DOTA-TATE is 200 MBq and the ligand content in the preparation should not exceed 0.05 mg. Therefore, when analyzing the limit of metallic impurities, e.g. Zn in the radionuclide precursor, similar values are obtained in both cases, i.e. maximum 37 ng and 40 ng per microgram of DOTA-TATE for lutetium-177 and gallium-68, respectively.
When the radiochemical purity is compared, the higher limit of permissible other forms of diagnostic radionuclide ([68Ga]gallium(III) ion: minimum 95%) than for the therapeutic radionuclide ([177Lu]Lutetium(III) ion: minimum 99%) does not result in a higher risk to the patient. Thus, 5% of other forms of a trivalent gallium-68 ion may result in the deposit of 10 MBq of this radionuclide in undesirable chemical form in non-target organs, while for 1% lutetium-177 it is as much as 74 MBq of uncontrolled chemical form. However, it must be noted that a stricter limit for the latter radionuclide is difficult to achieve due to the limitations of the analytical methods, which are characterized by an approximate 1% uncertainty of determination.
Bearing in mind that the differences in the profile of radionuclide contamination depend on the radionuclide production process [67], it is unlikely that uniform quality requirements for radionuclide precursors will be set in numerical terms. Each radionuclide precursor should be evaluated on a case-by-case basis, taking into account the physical characteristics of the radionuclide, its mode of irradiation and chemical processing as well as the envisaged clinical use and the dose planned for administration to the patient. This is clearly reflected in monographs referred in this Chapter. The monograph for 177Lu [59] applies to both the direct and indirect production routes of 177Lu in nuclear reactors and covers all quality aspects regardless the different specific radioactivity and impurity profiles. The decision is left to the producer of the final radiopharmaceutical preparation to use the appropriate solution for radiolabeling. However, the relevant information needs to be stated on the label. This is different in case of 68Ga, there are two different monographs specifying its quality requirements depending whether it’s generator [65] or accelerator produced [66]. One can expect that a similar individual approach applies to the future monographs for new theranostic radionuclides, for example 47Sc, which can be either accelerator or reactor produced [68].
Are the requirements for radiopharmaceutical precursors overregulated? With the development of new theranostic procedures involving radiopharmaceuticals, there is a need for proper qualitative evaluation of the final radiopharmaceutical preparation and both of the radiopharmaceutical precursors to ensure efficacy and safety of the treatment. An excellent example of the long pathway of a radiopharmaceutical, 111In-CP04, a peptide targeting the cholecystokinin-2 receptor, from the preclinical development over establishing the required pharmaceutical documentation to designing and submitting a clinical trial in patients with Medullary Thyroid Carcinoma, was recently presented [16]. All the quality aspects of CP04 as chemical precursor have been addressed in the IMPD in view of the quality and suitability of the radiolabeled preparation, 111In-CP04, in order to bring it to the clinic.
In this Chapter, the quality requirements applicable to radiopharmaceutical precursors in the context of their regulatory status in Europe were reviewed. EMA and Ph. Eur. provide public standards for manufacture and quality control of these precursors by establishing specifications and acceptance criteria. While in the case of radiopharmaceuticals with MA and CT regulations quite strictly define the quality and documentation requirements, such standards for in-house produced radiopharmaceuticals are still awaited.
Most companies have heard about the VUCA world that we live in today, but few have developed actionable strategies to thrive in this business environment that is entangled in
Insight-driven sales management is one of those powerful systems that can help companies thrive not only survive in this new business world.
\nTo understand this novel approach to sales management, a review of academic literature and practitioner reports was conducted to explore this shift in the business environment and how it will impact the sales process and how we manage it. This chapter will review the impact of data and advanced technologies such as Artificial Intelligence and machine learning on sales decisions and the characteristics of the digital-age sales teams, consumers, and business buyers. It will also discuss the future of the sales process (planning, coordinating, controlling, and motivating) and the sales management practices.
\nCompanies need to embrace the VUCA world and proactively manage it to capitalize on the many opportunities it represents and reduce the negative impact of threats that might arise. Sales organizations are the frontline forces that can help manage this new business world.
\nSales management teams need to use agility to manage volatility, information to manage uncertainty, restructuring to manage complexity, and experimentation to manage ambiguity as follows:
\n
\n
\n
\n
Those are the new rules for effective sales management in the future. \nTable 1\n defines the dimensions of the VUCA world and provides examples to demonstrate it and explain how to effectively address it.
\n\n | What it is | \nAn example | \nHow to effectively address it | \n
---|---|---|---|
\n | \nA diverse but interrelated set of information, processes, and procedures that require deep integrated analysis to be usable | \nInternational market penetration involves managing a very complex set of relationships, laws, regulations, financing options, and logistics issues | \nInternal standard operating procedures (SOPs) need to embrace the external environment perspective. Operations need to analyze the market information and integrate it in its practices through effective and efficient restructuring | \n
\n | \nLack of knowledge and inability to link antecedents and consequences of critical issues with limited ability to use lessons learnt to make future predictions | \nThe impact of new digital platforms on traditional media channels (TV, radio, and newspapers) has caused many shifts in consumer behavior that is impacting many industries such as media, telecomm, and entertainment | \nExperimentation is the way to manage ambiguity. The management should develop an effective system for anticipation and deployment of strategies that can handle the unknowns based on the integration of new trends and best practices | \n
\n | \nInstability that comes from frequent and unpredictable changes in the business environment | \nRaw material prices can be affected by many issues (such as political tensions, transportation costs, regulations, environmental issue, etc.) that cause it to be very volatile | \nAgility is the best way to handle volatility. Companies should focus on building controlled and well-planned slacks to allow for future flexibility and manage volatility | \n
\n | \nSituations are understood; antecedents and consequences can be correlated, but past experiences cannot be used to assess the ramifications and magnitude of the changes | \nThe war on terrorism generally suffers from uncertainty; we understand the root causes of terrorism, but not exactly when and how it will hit next | \nInformation based on new sources of data (both online and offline) coupled with insights are critical to managing uncertainty. Organizations need to embrace a new perspective on information use in business | \n
Managing the VUCA world [1].
We are living in a world where DATA is considered the new oil. Companies that will learn how to manage its internal and external customer data to develop insights to drive its sales process and its decision-making are those that will lead the way for the future sales management models.
\nIDC indicates in their study about “Worldwide Embedded and Intelligent Systems” that by 2020 the world will have more than 4 billion connected people, with $4 trillion in revenue opportunities, more than 25 million mobile applications, and more than 25 million embedded intelligent systems. All this will generate 50 trillion GB of data [2].
\nWe are now moving toward the Internet of things (IoT), where the physical and virtual worlds are integrated. We are already seeing many devices and applications that are gradually coming part of our life such as smart homes, driverless cars, smart personal assistants, and industrial robotics. At the same time, many companies are working on commercializing the Internet of everything (IoET). This is where people, applications, devices, sensors, and data are seamlessly integrated and used to generate revenue and create value.
\nThis explosion of connectivity and data will require a different type of sales management approach that can turn this data into valuable information that is used to create organizational knowledge that can be leveraged using new tools such as Artificial Intelligence (AI) and data science into customer insights.
\nSyam and Sharma indicated that part of the fourth industrial revolution is the integration of Artificial Intelligence (AI) and machine learning (ML) into the sales functions. They labeled this movement as the “Sales Renaissance.” They indicated that the impact will not be uniform across all sales situations, such that the higher the complexity of the sales process, the lower the impact of AI and ML on the salesperson. In such cases technology will augment the salesperson role but will not replace him/her. In such cases the salesperson is a knowledge broker. On the other hand, simple sales situations are good target for AI and ML to minimize the role of the salesperson or even replace him. They proposed that AI and ML can play a significant role in improving the efficiency and effectiveness of all the steps of the sales process including prospecting, pre-approach and approach, presentation, overcoming objections in closing stage, and follow-up [3].
\nSales teams will never relinquish its reliance in traditional salesmanship and relationship skills but will need to complement this with an intelligent use of the data and the insights that can be drawn out of it to bring the sales team efficiency and effectiveness to new heights that matches the new challenges presented by the VUCA world we live in.
\nThe following \nFigure 1\n clearly indicates that the world has passed the information age and the knowledge economy and is now moving toward insight-driven business models as the foundation of future competitive advantage. But the figure also shows that data is the foundation of this progression and evolution.
\nFrom data to insights.
William C. Moncrief in his paper titled “Are sales as we know it dying… or merely transforming?” argued that many galvanizing environmental factors have changed sales over the years (such as globalization, changing consumer habits, and automation), but the impact of social media effects on sales will present a leapfrog in sales transformation. The social media environment will be affected by and will affect all aspects of the sales organization [4]. With the information SM provides the analytic tools available (such as Facebook analytics, Socialbakers, etc.); sales teams have a very powerful new tool to support their sales efforts and in customer relationship building.
\nIn a case study developed by Bocconcelli et al. in 2017, they confirmed that small and medium enterprises (SMEs) can use different types of social media (SM) platforms (such as Facebook, YouTube, and LinkedIn) to manage the sales relationships with its distributors, customers, and business partners. SM as a valuable resource reduced constraints of time and space, enhanced communication, and provided more planned and proactive sales approach. Finally, SM effectiveness as sales resource depends on its integration with other SME sales resources [5].
\nThe future of sales management is to be insight driven and to be built on a solid foundation of data, information, and knowledge. This provides better understanding of relations, patterns, and principles to manage all of the process stakeholders—both the digital-age sales team and the digital-age consumers.
\nThe digital-age sales team has seven key attributes needed to remain at the top of the future sales management system. These attributes hold true regardless of the size or shape of sales operation [6].
Modern sales teams are
Modern sales teams are religious about
Modern sales teams focus on
The Customer Relationship Management (CRM) system: data such as Pipeline Analytics, commission forecasting, and sales effectiveness measures
The enterprise resources planning (ERP) system: data such as demand planning, pricing optimization, and contract management
The human resources information system (HRIS): data such as onboarding, coaching, and certification
The industry data such as territory optimization, route optimization, and underserved market segments
Modern sales teams deliver
Modern sales teams manage using leading KPIs: traditional lagging KPIs such as sales target achievement and deal profitability are not enough to effectively manage the digital-age sales teams. Leading KPIs such as number of calls made, number of visits, average duration of sales calls, etc. are forward-facing indicators that give a picture of the health of our sales process efficiency and effectiveness.
Modern sales teams continually monitor and tune their sales process: as sales teams continuously face new types of customers and new markets with challenging new needs, the sales process must be continually monitored and tweaked to match the evolving sales situations and requirements. Sales process elements such as inputs, non-value-adding steps, decision points, and control points need to be assessed and improved.
Modern sales teams encourage performance through
Our sales teams need to face today’s digital-age consumers. Those consumers are more complex and better equipped to deal with sales people. They are characterized by the following seven dimensions:
They are more
They are more
They are more
They are more
They are more
They are more
They are more on the
All those dimensions are driven by the inherent characteristics of the digital world we live in. this new consumer needs a new breed of sales people, tools, and processes to meet his needs, expectations, and higher levels of power.
\nThis new level of consumer power in the digital age is based on four sources: two individual-based power sources (demand- and information-based power) due to higher level of accessibility and information availability and two dynamic and complex network-based power sources (network- and crowd-based power) due to higher levels of connectivity and interactions on social media platforms [7].
\nDemand-based power is viewed as democratic voting power exercised by the consumer in different actions online, such as Facebook likes, YouTube views, Google searches, and Amazon purchases. Information-based power is related both to the consumer content consumption and content creation.
\nNetwork-based power comes from the consumer ability to add value beyond the original content through content dissemination, content completion, or content modifications. Finally, crowd-based power comes from pooled, mobilized, and structured resources that the individual consumer and the groups he belongs to can benefit.
\nThis escalating level of consumer power needs to be managed across the different areas of customer touch points and interactions both in the physical and digital worlds. That led to the redefinition of when and where the customer and the sales team connect.
\nSales management is about efficiently and effectively managing the customer
Traditional sales/marketing mental model [
As per Google, in the digital age, sales management needs to add a
New-age sales/marketing mental model [
In a survey of 5000 customers, Google found that online comparison shopping comes (54%) immediately after talking with the sales person (57%) as the main influencer in their buying decision (see \nFigure 4\n for the comparison shopping online and searching online (50%) rank among the top influences on the shoppers’ ultimate decision) [9].
\nWhat influences the shopper’s ultimate decision [
Savvy consumers are becoming increasingly fastidious and expect a tailored, personal shopping experience. Modern day consumers expect to be able to shop anywhere (home, in-store, at work, on the road), at any time (24 × 7), and from any device (computer, mobile phone, e-kiosk, etc.). They want the right product and the right price delivered at the right time. Consumer-focused retailers are working hard to meet these stringent demands across the different channels the consumer is using. This integrated customer shopping experience is formed by the new environment known as the
The future in retailing is in the tight and seamless integration of online and offline business practices into a new business model that cater to the new emerging consumer needs. Traditional brick-and-mortar outlets, pure e-tailer sites/applications, and brick-and-click (bricks-and-mortars that also have an online presence) players need to develop new omni-channel-based strategies. That is why traditional retailers are looking to go online and why e-tailers are looking at various options to establish a physical presence (lately AMAZON acquired a supermarket chain called WHOLE FOODS and established pilots for physical stores called AMAZON GO). The challenge is to find a seamless solution for both the customer experience and internal sales management processes.
\nThe omni-channel sales environment integrates both online and offline sales outlets including elements such as (1) online catalogs, (2) point of sale (POS) and payment systems, (3) mobile applications, (4) social media, (5) websites, (6) physical store, (7) near-filed communication (NFC) devices, (8) touch screen and tablets, and (9) digital screens. Those nine elements might see more options added to them in the future, so what we consider as complex sales environment today will be more and more complex in the future. That brings both opportunities and threats that sales management teams need to be aware of and ready for. This can be managed by adopting an integrated online to offline and offline to online (O2O) that meets the expectations and needs of the digital-age consumer [10].
\nCummins et al. define omni-channel marketing in a sales context as the synergetic integration of customer touch points and communication opportunities for the purpose of creating a unified brand experience regardless of channel, platform, or stage in the selling process. They developed a framework for the impact of omni-channel marketing on six sales dimensions [11]:
Sales contexts (B2C vs. B2B)
Impact of technology
Stages in the sales process
Impact on relationships
Impact on firm performance
The role of communication tools and platforms
Compared with buyers in the business-to-consumer (B2C) sector, business-to-business (B2B) buyers have been largely predictable in how they make buying decisions. But increasingly, that is no longer the case. Today, B2B buyers are behaving like consumers. They use online resources to collect information about the products, different suppliers, other buyers, and many more. This behavior reshapes the business buyers purchasing process, roles, and decision-making. This “consumerization” of B2B buying has made business customers more and more powerful. To maintain their balance of power in the process, sales professionals need to change their approach and become as digital as their customers [12].
\nOne major driver is the dramatic increase in the level of competition and disruption in the marketplace. The advent of more transparent marketplaces and the proliferation of online content and digital communities, combined with social media, allow buyers to increasingly self-educate and to process their purchases directly without dealing with a salesperson. According to the International Data Corporation (IDC), the majority of buying decisions (between 50 and 80%) are made prior to the engagement of the salesperson. Also 90% of B2B buying, decision-makers never respond to cold sales calls.
\nA recent study by Mckinsey & Company reported that the type of buying situation will have a big impact on the how B2B buyers value the involvement of the sales professional. In new-B=buy situations (where the buyer is researching a new product or service), 76% reported that it is helpful to engage with a salesperson. In the case of modified re-buy, the figure dropped to 52%. Finally, in the case of straight re-buy of the same product/service, only 15% of buyers saw value of dealing with the salesperson [13].
\nThe above reviewed studies clearly indicate that traditional sales organizations face the risk of obsolescence as buyers become more self-sufficient and more digital savvy. Basic sales interactions can be easily handled using online resources/portals such as Alibaba. Sales organizations need to focus more on managing complex purchasing situations where their value can be appreciated.
\nManaging the digital-age B2B buyers requires the adaption of digital selling approach that integrates new skills, tools, and processes. Companies like SAP and XEROX adopted a methodology that called for the establishment of a digital sales center of excellence (CoE) that provides leadership, best practices, skills, processes, technologies, and other kinds of support to their sales teams.
\nThe digital sales CoE develops the following six competencies [12]:
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With a digital selling CoE in place, a company’s sales operations can become much more efficient and effective and substantially improve the return sales delivered to the enterprise, while meeting the expectations and needs of the digital-age B2B buyers. The digital selling CoE uses sales enablement process and tools to deliver on its promise.
\nThere is no question that technology in the digital age has rapidly advanced the way we approach, negotiate, and close new opportunities. Sales enablement which is the process of providing the sales organization with
Emerging technologies have made it possible to see what, when, and how the sales process, sales/marketing content, and customer interactions/feedback are working. This provides a solid foundation for digital sales transformation.
\nAnalytics are at the core of sales enablement tools and are key to sales teams’ performance improvement. When the sales leaders use analytical insights, they can link what the marketing team is pushing (e.g., content) out and what the sales team is pulling in (e.g., conversions/sales).
\nDigital sales organizations need to develop an effective content strategy that is based on solid understanding on how the offered content is being used both by the sales team members and the customers. Tracking and analyzing what content is being accessed, how often, at what time, and at what stage in the sales process can provide the needed insights for sales management.
\nFollowing are the major advantages that the sales enablement tools offer and the importance of analytics to each [14]:
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Sales management is at the forefront of management systems development due to its direct link to the customer—the ultimate prize of sales. As new business models evolve, sales management needs to add new dimensions to the sales process and needs to embrace new ways to manage its traditional ones. So sales management has to work in a broader and newer environment, in coexistence with the traditional lines.
\nTraditionally, there are four basic elements of sales management [15]. All of them can be enhanced when augmented by digitization as indicated below:
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But gaining control over the sales team is not a simple task. Studies have shown that sales force has opportunism tendencies to gain short-term personal advantages over the long-term firm or team gains. This opportunism takes two main forms: shirking and influence activities. In their article on regaining control of the sales force, Kim and Jung studied 304 Korean automobile dealers and found that outcome controls and behavioral controls have different effects depending on the type of sales opportunism.
Output controls (preset goals to reward or penalize the sales force) mitigate sales control loss when it is matched with shirking behavior (evasion of obligation and withholding efforts), while it aggravates control loss when matched with salespeople influence activities (intentional acts to persuade the employer to take actions that that will be in their own advantage). On the other hand, behavior control (rules and procedures to reward and penalize sales force) mitigates control loss when matched with salesperson’s influence activities and aggravates control loss when matched with shirking activities [16].
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In 2017, Reid et al. studied the use of 68 sales management practices (SMPs)—such as forecasting, training, incentive pay, evaluations, etc.—covering seven key managerial areas building on the seminal work done by Dubinsky and Barry in 1982. Those sales management areas are (1) sales planning, (2) organization and selection, (3) training, (4) sales compensation, (5) supervision and evaluation, (6) control of sales force performance, and (7) sales technology. They identified a list of 21 challenges that sales managers face today and concluded that the low level of technology use by sales organizations amplifies the impact of those challenges [17].
\nTechnology today is being used in the field by sales people for data collection and automation of sales tasks but is not as prevalent when it comes to managing and supporting the sales management practices (SMPs).
\nHence, there is need for higher level of adoption to meet the need of the new breed of digital-age sales managers that is emerging. They are data hungry and technology savvy. This new breed also behaves more like a modern-day sports coach, craving sales performance insight. Digital-age sales managers live by a new mantra:
With the integration of people and technology, sales managers need to continually develop their skills, process, and tools to achieve results in the VUCA world. This can be can only be achieved when they develop systems that fully integrate the seven sales management areas and not to deal with them as discrete or sequential steps. For example, this means using the control system (KPIs) to motivate the team and the coordination system to optimize the planning process.
\nIn 2018, Panagopoulos et al. discussed the importance of boosting sales force morale in highly dynamic complex markets. They used the job demand-resource (JD-R) theory as the basis for their model. They studied the impact of market demands (customer purchase complexity and market dynamism) on sales force morale that drives key outcomes (sales force turnover and sales force productivity). Three job resources (sales capabilities training, firms product portfolio depth, and sales units’ cross-functional cooperation) were used as moderating variables for the relationship between market demands and sales force morale [18].
\nIn the longitudinal study they conducted over 2 years, they found that an increase of morale by one point on a five-point scale improves sales force productivity by €226,834 of operating revenues per salesperson, while it lowers turnover rate by 5%.
\nFinally, since the driver of any sales management process and the target is the efficient and effective sales team, the following section will demonstrate how can we
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The problem with the sales revenue metric is that it is rearview facing. It is often referred to as a “
For example, this can be achieved by having the sales teams:
Qualify leads within 24 hours of creation
Create a certain number of pre-pipe opportunities each week
Meet a target of “meaningful” sales calls each week
Book more meetings or demos with the right level of contact each week
Build a regular monthly or quarterly cadence of deal closure
These leading sales metrics need to be combined into a regular cadence of daily, weekly, monthly, or even quarterly targets. This would allow the sales manager to drive the sales behaviors right across the sales process that delivers sustained success.
\nSales metrics also need to follow different time intervals. This allows for balancing the short-term and long-term monitoring of the performance. This approach is called metrics pacing. There are four pacing methods:
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This pacing approach for sales target setting allows for the flexibility in adapting the targets for different sales teams’ capabilities and different client buying situations. This customized approach to target setting provides a more personalized approach that is more fit with today’s sales people mentality that does not approach the one-size-fits-all traditional approach.
\nBuilding on the need to use a combination of leading and lagging metrics, calculating the Salesperson Future Value (SFV) to the firm can add a whole new dimension that supports today’s sales managers challenging task of encouraging their teams while managing their investment in the team members to maximize the sales team performance and the firm return. Kumar, Sunder, and Leone proposed a system to measure the Salesperson Future Value and its drivers. They defined SFV as the net present value (NPV) of future cash flows from the salesperson’s customers after accounting for appropriate costs associated with the salesperson. The study identified the drivers of SFV as training interventions (both for growth-related and task-related key skill areas) and incentives (both monetary and non-monetary). They used the salesperson tenure, region, market size, and competition level as control variables. They found that using current revenue generated by the sales person can lead to the wrong decision about the SFV in 27% of the cases and that the correlation between revenue generated and SFV is only 0.64. Effective management of the drivers of SFV for different segments of salespeople based on this leading indicator can help the organization optimize its resources and achieve its strategic sales objectives [20].
\nFinally, encouragement is reinforced with celebrating success. The digital-age sales manager knows that publicly recognizing achievement will not only encourage the winners to do more to stay at the top but will motivate the rest of the team to join the winner ranks.
\nThe traditional once-a-year sales competitions that uses only sales target achievement (lagging indicator) does provide the foundation to develop a culture of continuous improvement. Hence using multiple year-round competitions using leading indicators is a better tool to maintain a highly motivated sales team.
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One of the approaches used to improve salespeople compliance with the sales process is to incorporate a set of “sales behaviors” metrics (leading indicators) as part of the sales management dashboard. This addition of key behavioral indicators (KBIs) to the traditional business oriented key performance indicators (KPIs) such as revenues and linking them to have a new definition of winners and losers is a critical part of the digital-age sales management approach.
\nThe correlation between achievement of behavioral targets and revenue targets generates four profiles/segments of sales performers that not only focus on target achievements but in sustainability of delivering results while balancing the short-term and long-term outcomes.
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This approach of tailored support to sales team will provide higher levels of engagement and more user adoption of the sales management tools. Digital-age sales managers transform the Customer Relationship Management (CRM) system from a passive data repository that is otherwise easily mistaken for a management reporting tool. They turn the CRM system into a real-time sales engagement tool.
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The data savvy sales manager knows they can utilize the achievement of leading sales behaviors mapped against a deal to determine its true health. Utilizing machine learning, they drive the Digital Sales Management System to provide a real-time deal health prediction for every single deal.
\nFinally, coaching to improve sales force performance beyond deal closing can be achieved by incorporating innovation implementation into the sales organization. Wang and Miao proved that sales force creativity impact on performance is fully mediated by innovation implementation. The relationship between creativity and innovation is moderated by innovative organization culture and behavior-based supervision. This is where proactive coaching that is guided by real-time data and analytics can lead to higher levels of sales force performance. The coaching should focus on market orientation (MO) (customer orientation, competitor orientation, and inter-functional coordination) to spur sales force creativity [21].
\nThe VUCA world is dramatically changing the face of sales management. The digital-age consumer and B2B buyers need digital-age sales managers and organizations that continuously and actively map out and manage their sales process. Sales management today needs to be insight-driven, agile, experimentation based, and flexible.
\nNew tools that collect, integrate, and analyze customer data from internal and external sources provide the foundation for the insight-driven sales management. This includes technologies such as analytics (Web, social, and mobile), Artificial Intelligence, machine learning, dynamic content management, and user experience (UX).
\nThose tools might represent a risk for some basic sales jobs that is focused on order taking for simple products but represent a great opportunity to augment salespeople that manage complex and high-margin sales to improve their efficiency and effectiveness.
\nNew sales management practices need to manage the omni-channel approach to customer touch points because customers today expect to engage with the company sales team Any-Where, Any-Time, Any-Device (AWATAD). They continuously move between the online and offline worlds (O2O) during the buying decision-making process. This represents a major opportunity for data collection to develop real-time insights beyond the traditional consumer market research studies.
\nThe modern-day sales managers need to use leading indicators (not only traditional sales revenue lagging indicators) to measure progress along the sales process end-to-end path, to make these steps transparent to the whole team and motivate them to overachieve. They make success transparent and build a culture of winning based on creativity and innovation. They use the data insights and technology to provide intelligent coaching in real time.
\nThe digital-age sales manager thinks and behaves like a modern sports coach and brings science into the art of selling.
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These physiological events occur smoothly in normal healthy individual and/or under normal conditions. However, in certain cases, these molecular events are retarded resulting in hard-to-heal or chronic wounds arising from several factors such as poor venous return, underlying physiological or metabolic conditions such as diabetes as well as external factors such as poor nutrition. In most cases, such wounds are infected and infection also presents as another complicating phenomenon which triggers inflammatory reactions, therefore delaying wound healing. There has therefore been recent interests and significant efforts in preventing and actively treating wound infections by directly targeting infection causative agents through direct application of antimicrobial agents either alone or loaded into dressings (medicated). These have the advantage of overcoming challenges such as poor circulation in diabetic and leg ulcers when administered systemically and also require lower amounts to be applied compared to that required via oral or iv administration. This chapter will review and evaluate various antimicrobial agents used to target infected wounds, the means of delivery, and current state of the art, including commercially available dressings. Data sources will include mainly peer-reviewed literature, clinical trials and reports, patents as well as government reports where available.",book:{id:"5290",slug:"wound-healing-new-insights-into-ancient-challenges",title:"Wound Healing",fullTitle:"Wound Healing - New insights into Ancient Challenges"},signatures:"Omar Sarheed, Asif Ahmed, Douha Shouqair and Joshua Boateng",authors:[{id:"183108",title:"Dr.",name:"Joshua",middleName:null,surname:"Boateng",slug:"joshua-boateng",fullName:"Joshua Boateng"},{id:"183399",title:"Dr.",name:"Omar",middleName:null,surname:"Sarheed",slug:"omar-sarheed",fullName:"Omar Sarheed"},{id:"188082",title:"Mr.",name:"Asif",middleName:null,surname:"Ahmed",slug:"asif-ahmed",fullName:"Asif Ahmed"},{id:"188083",title:"Ms.",name:"Douha",middleName:null,surname:"Shouqair",slug:"douha-shouqair",fullName:"Douha Shouqair"}]},{id:"51825",doi:"10.5772/64611",title:"Roles of Matrix Metalloproteinases in Cutaneous Wound Healing",slug:"roles-of-matrix-metalloproteinases-in-cutaneous-wound-healing",totalDownloads:3629,totalCrossrefCites:20,totalDimensionsCites:39,abstract:"Wound healing is a complex process that consists of hemostasis and inflammation, angiogenesis, re-epithelialization, and tissue remodeling. Matrix metalloproteinases (MMPs) play important roles in wound healing, and their dysregulation leads to prolonged inflammation and delayed wound healing. There are 24 MMPs in humans, and each MMP exists in three forms, of which only the active MMPs play a role in the pathology or repair of wounds. The current methodology does not distinguish between the three forms of MMPs, making it challenging to investigate the roles of MMPs in pathology and wound repair. We used a novel MMP-inhibitor-tethered affinity resin that binds only the active form of MMPs, from which we identified and quantified active MMP-8 and active MMP-9 in a murine diabetic model with delayed wound healing. We showed that up-regulation of active MMP-9 plays a detrimental role whereas active MMP-8 is involved in repairing the wound in diabetic mice. These studies identified MMP-9 as a novel target for therapeutic intervention in the treatment of chronic wounds. A selective inhibitor of MMP-9 that leaves MMP-8 unaffected would provide the most effective therapy and represents a promising strategy for therapeutic intervention in the treatment of diabetic foot ulcers.",book:{id:"5290",slug:"wound-healing-new-insights-into-ancient-challenges",title:"Wound Healing",fullTitle:"Wound Healing - New insights into Ancient Challenges"},signatures:"Trung T. Nguyen, Shahriar Mobashery and Mayland Chang",authors:[{id:"183405",title:"Prof.",name:"Mayland",middleName:null,surname:"Chang",slug:"mayland-chang",fullName:"Mayland Chang"},{id:"191152",title:"Mr.",name:"Trung",middleName:null,surname:"Nguyen",slug:"trung-nguyen",fullName:"Trung Nguyen"},{id:"191153",title:"Prof.",name:"Shahriar",middleName:null,surname:"Mobashery",slug:"shahriar-mobashery",fullName:"Shahriar Mobashery"}]},{id:"63675",doi:"10.5772/intechopen.81208",title:"Wound Healing: Contributions from Plant Secondary Metabolite Antioxidants",slug:"wound-healing-contributions-from-plant-secondary-metabolite-antioxidants",totalDownloads:1331,totalCrossrefCites:7,totalDimensionsCites:20,abstract:"Plants by their genetic makeup possess an innate ability to synthesize a wide variety of phytochemicals that help them to perform their normal physiological functions and/or to protect themselves from microbial pathogens and animal herbivores. The synthesis of these phytochemicals presents the plants their natural tendency to respond to environmental stress conditions. These phytochemicals are classified either as primary or secondary metabolites. The secondary metabolites have been identified in plants as alkaloids, terpenoids, phenolics, anthraquinones, and triterpenes. These plant-based compounds are believed to have diverse medicinal properties including antioxidant properties. Plants have therefore been a potential source of antioxidants which have received a great deal of attention since increased oxidative stress has been identified as a major causative factor in the development and progression of several life-threatening diseases, including neurodegenerative and cardiovascular diseases and wound infection. Consequently, many medicinal plants have been cited and known to effect wound healing and antioxidant properties. This chapter briefly reviews antioxidant properties of medicinal plants to highlight the important roles medicinal plants play in wound healing.",book:{id:"7046",slug:"wound-healing-current-perspectives",title:"Wound Healing",fullTitle:"Wound Healing - Current Perspectives"},signatures:"Victor Y.A. Barku",authors:[{id:"261027",title:"Prof.",name:"Victor Y. A.",middleName:null,surname:"Barku",slug:"victor-y.-a.-barku",fullName:"Victor Y. A. Barku"}]},{id:"66793",doi:"10.5772/intechopen.85020",title:"The Impact of Biofilm Formation on Wound Healing",slug:"the-impact-of-biofilm-formation-on-wound-healing",totalDownloads:1434,totalCrossrefCites:7,totalDimensionsCites:16,abstract:"Chronic wounds represent an important challenge for wound care and are universally colonized by bacteria. These bacteria can form biofilm as a survival mechanism that confers the ability to resist environmental stressors and antimicrobials due to a variety of reasons, including low metabolic activity. Additionally, the exopolymeric substance (EPS) contained in biofilm acts as a mechanical barrier to immune system cells, leading to collateral damage in the surrounding tissue as well as chronic inflammation, which eventually will delay healing of the wound. This chapter will discuss current knowledge on biofilm formation, its presence in acute and chronic wounds, how biofilm affects antibiotic resistance and tolerance, as well as the wound healing process. We will also discuss proposed methods to eliminate biofilm and improve wound healing despite its presence, including basic science and clinical studies regarding these matters.",book:{id:"7046",slug:"wound-healing-current-perspectives",title:"Wound Healing",fullTitle:"Wound Healing - Current Perspectives"},signatures:"Rafael A. Mendoza, Ji-Cheng Hsieh and Robert D. Galiano",authors:[{id:"253607",title:"M.D.",name:"Rafael",middleName:null,surname:"Mendoza",slug:"rafael-mendoza",fullName:"Rafael Mendoza"},{id:"254018",title:"Dr.",name:"Robert",middleName:null,surname:"Galiano",slug:"robert-galiano",fullName:"Robert Galiano"},{id:"271116",title:"Mr.",name:"Ji-Cheng",middleName:null,surname:"Hsieh",slug:"ji-cheng-hsieh",fullName:"Ji-Cheng Hsieh"}]},{id:"63086",doi:"10.5772/intechopen.80215",title:"Medicinal Plants in Wound Healing",slug:"medicinal-plants-in-wound-healing",totalDownloads:2901,totalCrossrefCites:7,totalDimensionsCites:15,abstract:"Wound healing process is known as interdependent cellular and biochemical stages which are in trying to improve the wound. Wound healing can be defined as stages which is done by body and delayed in wound healing increases chance of microbial infection. Improved wound healing process can be performed by shortening the time needed for healing or lowering the inappropriate happens. The drugs were locally or systemically administrated in order to help wound healing. Antibiotics, antiseptics, desloughing agents, extracts, etc. have been used in order to wound healing. Some synthetic drugs are faced with limitations because of their side effects. Plants or combinations derived from plants are needed to investigate identify and formulate for treatment and management of wound healing. There is increasing interest to use the medicinal plants in wound healing because of lower side effects and management of wounds over the years. Studies have shown that medicinal plants improve wound healing in diabetic, infected and opened wounds. The different mechanisms have been reported to improve the wound healing by medicinal plants. In this chapter, some medicinal plants and the reported mechanisms will be discussed.",book:{id:"7046",slug:"wound-healing-current-perspectives",title:"Wound Healing",fullTitle:"Wound Healing - Current Perspectives"},signatures:"Mohammad Reza Farahpour",authors:[{id:"253340",title:"Prof.",name:"Mohammadreza",middleName:null,surname:"Farahpour",slug:"mohammadreza-farahpour",fullName:"Mohammadreza Farahpour"}]}],mostDownloadedChaptersLast30Days:[{id:"55736",title:"Haemodynamic Monitoring in the Intensive Care Unit",slug:"haemodynamic-monitoring-in-the-intensive-care-unit",totalDownloads:3369,totalCrossrefCites:1,totalDimensionsCites:1,abstract:"Monitoring is a cognitive aid that allows clinicians to detect the nature and extent of pathology and helps assessment of response to therapy. The cardiovascular system is the most commonly monitored organ system in the critical care setting. It helps identify the presence and nature of shock and guides response to resuscitation by detection of cardiac rate and rhythm, evaluation of volume state, cardiac contractility and systemic vascular resistance. Newer technologies allow greater assessment of oxygen delivery to vulnerable tissues. We discuss the nature, history, modalities and interpretation of the most commonly available haemodynamic monitoring methods in clinical use currently.",book:{id:"5756",slug:"intensive-care",title:"Intensive Care",fullTitle:"Intensive Care"},signatures:"Mainak Majumdar",authors:[{id:"86678",title:"Dr.",name:"Mainak",middleName:null,surname:"Majumdar",slug:"mainak-majumdar",fullName:"Mainak Majumdar"}]},{id:"51825",title:"Roles of Matrix Metalloproteinases in Cutaneous Wound Healing",slug:"roles-of-matrix-metalloproteinases-in-cutaneous-wound-healing",totalDownloads:3628,totalCrossrefCites:20,totalDimensionsCites:37,abstract:"Wound healing is a complex process that consists of hemostasis and inflammation, angiogenesis, re-epithelialization, and tissue remodeling. Matrix metalloproteinases (MMPs) play important roles in wound healing, and their dysregulation leads to prolonged inflammation and delayed wound healing. There are 24 MMPs in humans, and each MMP exists in three forms, of which only the active MMPs play a role in the pathology or repair of wounds. The current methodology does not distinguish between the three forms of MMPs, making it challenging to investigate the roles of MMPs in pathology and wound repair. We used a novel MMP-inhibitor-tethered affinity resin that binds only the active form of MMPs, from which we identified and quantified active MMP-8 and active MMP-9 in a murine diabetic model with delayed wound healing. We showed that up-regulation of active MMP-9 plays a detrimental role whereas active MMP-8 is involved in repairing the wound in diabetic mice. These studies identified MMP-9 as a novel target for therapeutic intervention in the treatment of chronic wounds. A selective inhibitor of MMP-9 that leaves MMP-8 unaffected would provide the most effective therapy and represents a promising strategy for therapeutic intervention in the treatment of diabetic foot ulcers.",book:{id:"5290",slug:"wound-healing-new-insights-into-ancient-challenges",title:"Wound Healing",fullTitle:"Wound Healing - New insights into Ancient Challenges"},signatures:"Trung T. Nguyen, Shahriar Mobashery and Mayland Chang",authors:[{id:"183405",title:"Prof.",name:"Mayland",middleName:null,surname:"Chang",slug:"mayland-chang",fullName:"Mayland Chang"},{id:"191152",title:"Mr.",name:"Trung",middleName:null,surname:"Nguyen",slug:"trung-nguyen",fullName:"Trung Nguyen"},{id:"191153",title:"Prof.",name:"Shahriar",middleName:null,surname:"Mobashery",slug:"shahriar-mobashery",fullName:"Shahriar Mobashery"}]},{id:"63086",title:"Medicinal Plants in Wound Healing",slug:"medicinal-plants-in-wound-healing",totalDownloads:2898,totalCrossrefCites:7,totalDimensionsCites:15,abstract:"Wound healing process is known as interdependent cellular and biochemical stages which are in trying to improve the wound. Wound healing can be defined as stages which is done by body and delayed in wound healing increases chance of microbial infection. Improved wound healing process can be performed by shortening the time needed for healing or lowering the inappropriate happens. The drugs were locally or systemically administrated in order to help wound healing. Antibiotics, antiseptics, desloughing agents, extracts, etc. have been used in order to wound healing. Some synthetic drugs are faced with limitations because of their side effects. Plants or combinations derived from plants are needed to investigate identify and formulate for treatment and management of wound healing. There is increasing interest to use the medicinal plants in wound healing because of lower side effects and management of wounds over the years. Studies have shown that medicinal plants improve wound healing in diabetic, infected and opened wounds. The different mechanisms have been reported to improve the wound healing by medicinal plants. In this chapter, some medicinal plants and the reported mechanisms will be discussed.",book:{id:"7046",slug:"wound-healing-current-perspectives",title:"Wound Healing",fullTitle:"Wound Healing - Current Perspectives"},signatures:"Mohammad Reza Farahpour",authors:[{id:"253340",title:"Prof.",name:"Mohammadreza",middleName:null,surname:"Farahpour",slug:"mohammadreza-farahpour",fullName:"Mohammadreza Farahpour"}]},{id:"67217",title:"Nursing Implications in the ECMO Patient",slug:"nursing-implications-in-the-ecmo-patient",totalDownloads:2528,totalCrossrefCites:3,totalDimensionsCites:3,abstract:"Effective care and positive outcomes of the extracorporeal membrane oxygenation (ECMO) patient necessitate optimal interdisciplinary management from the healthcare team, including expert care from specially trained registered nurses (RNs). It is incumbent upon the RN caring for the ECMO patient to excel in both time management and assessment skills, as this population often demands care delivery at the pinnacle of intensive care unit (ICU) acuity. Astute and nuanced monitoring of neurological status, bleeding risk with potential (often massive) transfusions, poor hemodynamics, and integrity of the ECMO pump itself are only the few specialized areas of focus that must share priority with traditional nursing considerations involving the critically ill, such as prevention of pressure injuries and bloodstream infections. These high-intensity medical foci must be balanced with ethical considerations, as the ultimate goal of returning the patient to their normal life is not always possible. These demands highlight the dynamic proficiency of the RN caring for the ECMO patient. The following chapter will highlight the importance of specialized nursing care in the critically ill patient supported with ECMO.",book:{id:"7878",slug:"advances-in-extracorporeal-membrane-oxygenation-volume-3",title:"Advances in Extracorporeal Membrane Oxygenation",fullTitle:"Advances in Extracorporeal Membrane Oxygenation - Volume 3"},signatures:"Alex Botsch, Elizabeth Protain, Amanda R. Smith and Ryan Szilagyi",authors:[{id:"298623",title:"Mr.",name:"Alexander",middleName:null,surname:"Botsch",slug:"alexander-botsch",fullName:"Alexander Botsch"}]},{id:"66239",title:"Echocardiography Evaluation in ECMO Patients",slug:"echocardiography-evaluation-in-ecmo-patients",totalDownloads:2184,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"Extracorporeal membrane oxygenation (ECMO) is a special form of organ support for selected cases of cardiovascular and severe respiratory failure. Echocardiography is a diagnostic and monitoring tool widely used in all aspects of ECMO support. The pathophysiology of ECMO, and its distinct effects on cardiorespiratory physiology, requires an echocardiographer with high skills to understand the interaction between the ECMO and the patient. In this chapter, we present the main application of echocardiography in ECMO patients and some general concepts on the ECMO working. ECMO, such as the standard cardiopulmonary bypass employed in cardiac surgery, V-V (veno-venous), can support the insufficient respiratory system by oxygenating and removing carbon dioxide from the blood. VA-ECMO (venous-arterial) can support haemodynamics by providing mechanical circulatory assistance. Today, ECMO can be used as bridge to decision, waiting for the development of the clinical conditions to support with other devices the evolution of cardiorespiratory failure or stop the assistance. Echocardiography (transthoracic (TTE) or transoesophageal (TOE)) can be used primarily to take decisions regarding appropriateness of ECMO support, therefore to control cannula insertion and confirm final position, to modify number and position of the cannulae in case of malfunctioning of these, and, finally, to assess clinical progress and suitability for weaning from ECMO.",book:{id:"7878",slug:"advances-in-extracorporeal-membrane-oxygenation-volume-3",title:"Advances in Extracorporeal Membrane Oxygenation",fullTitle:"Advances in Extracorporeal Membrane Oxygenation - Volume 3"},signatures:"Luigi Tritapepe, Ernesto Greco and Carlo Gaudio",authors:[{id:"284893",title:"Prof.",name:"Luigi",middleName:null,surname:"Tritapepe",slug:"luigi-tritapepe",fullName:"Luigi Tritapepe"},{id:"294005",title:"Prof.",name:"Ernesto",middleName:null,surname:"Greco",slug:"ernesto-greco",fullName:"Ernesto Greco"},{id:"294006",title:"Prof.",name:"Carlo",middleName:null,surname:"Gaudio",slug:"carlo-gaudio",fullName:"Carlo Gaudio"}]}],onlineFirstChaptersFilter:{topicId:"173",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:8,limit:8,total:0},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:11,numberOfPublishedChapters:91,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:108,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:33,numberOfPublishedChapters:332,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:14,numberOfPublishedChapters:145,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:11,numberOfPublishedChapters:142,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:124,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:112,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:22,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:12,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:"2753-6580",doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}},{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. 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He previously worked as a post-doctoral fellow at the Ben-Gurion University of Negev, Israel; University of the Free State, South Africa; and Central University of Technology Bloemfontein, South Africa. He obtained his Ph.D. in Organic Chemistry from Nagaoka University of Technology, Japan. He has published more than seventy-four journal articles and attended several national and international conferences as speaker and chair. Dr. Kendrekar has received many international awards. He has several funded projects, namely, anti-malaria drug development, MRSA, and SARS-CoV-2 activity of curcumin and its formulations. He has filed four patents in collaboration with the University of Central Lancashire and Mayo Clinic Infectious Diseases. His present research includes organic synthesis, drug discovery and development, biochemistry, nanoscience, and nanotechnology.",institutionString:"Visiting Scientist at Lipid Nanostructures Laboratory, Centre for Smart Materials, School of Natural Sciences, University of Central Lancashire",institution:null},{id:"428125",title:"Dr.",name:"Vinayak",middleName:null,surname:"Adimule",slug:"vinayak-adimule",fullName:"Vinayak Adimule",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/428125/images/system/428125.jpg",biography:"Dr. Vinayak Adimule, MSc, Ph.D., is a professor and dean of R&D, Angadi Institute of Technology and Management, India. He has 15 years of research experience as a senior research scientist and associate research scientist in R&D organizations. He has published more than fifty research articles as well as several book chapters. He has two Indian patents and two international patents to his credit. Dr. Adimule has attended, chaired, and presented papers at national and international conferences. He is a guest editor for Topics in Catalysis and other journals. He is also an editorial board member, life member, and associate member for many international societies and research institutions. His research interests include nanoelectronics, material chemistry, artificial intelligence, sensors and actuators, bio-nanomaterials, and medicinal chemistry.",institutionString:"Angadi Institute of Technology and Management",institution:null},{id:"284317",title:"Prof.",name:"Kantharaju",middleName:null,surname:"Kamanna",slug:"kantharaju-kamanna",fullName:"Kantharaju Kamanna",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/284317/images/21050_n.jpg",biography:"Prof. K. Kantharaju has received Bachelor of science (PCM), master of science (Organic Chemistry) and Doctor of Philosophy in Chemistry from Bangalore University. He worked as a Executive Research & Development @ Cadila Pharmaceuticals Ltd, Ahmedabad. He received DBT-postdoc fellow @ Molecular Biophysics Unit, Indian Institute of Science, Bangalore under the supervision of Prof. P. Balaram, later he moved to NIH-postdoc researcher at Drexel University College of Medicine, Philadelphia, USA, after his return from postdoc joined NITK-Surthakal as a Adhoc faculty at department of chemistry. Since from August 2013 working as a Associate Professor, and in 2016 promoted to Profeesor in the School of Basic Sciences: Department of Chemistry and having 20 years of teaching and research experiences.",institutionString:null,institution:{name:"Rani Channamma University, Belagavi",country:{name:"India"}}},{id:"158492",title:"Prof.",name:"Yusuf",middleName:null,surname:"Tutar",slug:"yusuf-tutar",fullName:"Yusuf Tutar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/158492/images/system/158492.jpeg",biography:"Prof. Dr. Yusuf Tutar conducts his research at the Hamidiye Faculty of Pharmacy, Department of Basic Pharmaceutical Sciences, Division of Biochemistry, University of Health Sciences, Turkey. He is also a faculty member in the Molecular Oncology Program. He obtained his MSc and Ph.D. at Oregon State University and Texas Tech University, respectively. He pursued his postdoctoral studies at Rutgers University Medical School and the National Institutes of Health (NIH/NIDDK), USA. His research focuses on biochemistry, biophysics, genetics, molecular biology, and molecular medicine with specialization in the fields of drug design, protein structure-function, protein folding, prions, microRNA, pseudogenes, molecular cancer, epigenetics, metabolites, proteomics, genomics, protein expression, and characterization by spectroscopic and calorimetric methods.",institutionString:"University of Health Sciences",institution:null},{id:"180528",title:"Dr.",name:"Hiroyuki",middleName:null,surname:"Kagechika",slug:"hiroyuki-kagechika",fullName:"Hiroyuki Kagechika",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/180528/images/system/180528.jpg",biography:"Hiroyuki Kagechika received his bachelor’s degree and Ph.D. in Pharmaceutical Sciences from the University of Tokyo, Japan, where he served as an associate professor until 2004. He is currently a professor at the Institute of Biomaterials and Bioengineering (IBB), Tokyo Medical and Dental University (TMDU). From 2010 to 2012, he was the dean of the Graduate School of Biomedical Science. Since 2012, he has served as the vice dean of the Graduate School of Medical and Dental Sciences. He has been the director of the IBB since 2020. Dr. Kagechika’s major research interests are the medicinal chemistry of retinoids, vitamins D/K, and nuclear receptors. He has developed various compounds including a drug for acute promyelocytic leukemia.",institutionString:"Tokyo Medical and Dental University",institution:{name:"Tokyo Medical and Dental University",country:{name:"Japan"}}},{id:"94311",title:"Prof.",name:"Martins",middleName:"Ochubiojo",surname:"Ochubiojo Emeje",slug:"martins-ochubiojo-emeje",fullName:"Martins Ochubiojo Emeje",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/94311/images/system/94311.jpeg",biography:"Martins Emeje obtained a BPharm with distinction from Ahmadu Bello University, Nigeria, and an MPharm and Ph.D. from the University of Nigeria (UNN), where he received the best Ph.D. award and was enlisted as UNN’s “Face of Research.” He established the first nanomedicine center in Nigeria and was the pioneer head of the intellectual property and technology transfer as well as the technology innovation and support center. Prof. Emeje’s several international fellowships include the prestigious Raman fellowship. He has published more than 150 articles and patents. He is also the head of R&D at NIPRD and holds a visiting professor position at Nnamdi Azikiwe University, Nigeria. He has a postgraduate certificate in Project Management from Walden University, Minnesota, as well as a professional teaching certificate and a World Bank certification in Public Procurement. Prof. Emeje was a national chairman of academic pharmacists in Nigeria and the 2021 winner of the May & Baker Nigeria Plc–sponsored prize for professional service in research and innovation.",institutionString:"National Institute for Pharmaceutical Research and Development",institution:{name:"National Institute for Pharmaceutical Research and Development",country:{name:"Nigeria"}}},{id:"436430",title:"Associate Prof.",name:"Mesut",middleName:null,surname:"Işık",slug:"mesut-isik",fullName:"Mesut Işık",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/436430/images/19686_n.jpg",biography:null,institutionString:null,institution:{name:"Bilecik University",country:{name:"Turkey"}}},{id:"268659",title:"Ms.",name:"Xianquan",middleName:null,surname:"Zhan",slug:"xianquan-zhan",fullName:"Xianquan Zhan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/268659/images/8143_n.jpg",biography:"Dr. Zhan received his undergraduate and graduate training in the fields of preventive medicine and epidemiology and statistics at the West China University of Medical Sciences in China during 1989 to 1999. He received his post-doctoral training in oncology and cancer proteomics for two years at the Cancer Research Institute of Human Medical University in China. In 2001, he went to the University of Tennessee Health Science Center (UTHSC) in USA, where he was a post-doctoral researcher and focused on mass spectrometry and cancer proteomics. Then, he was appointed as an Assistant Professor of Neurology, UTHSC in 2005. He moved to the Cleveland Clinic in USA as a Project Scientist/Staff in 2006 where he focused on the studies of eye disease proteomics and biomarkers. He returned to UTHSC as an Assistant Professor of Neurology in the end of 2007, engaging in proteomics and biomarker studies of lung diseases and brain tumors, and initiating the studies of predictive, preventive, and personalized medicine (PPPM) in cancer. In 2010, he was promoted to Associate Professor of Neurology, UTHSC. Currently, he is a Professor at Xiangya Hospital of Central South University in China, Fellow of Royal Society of Medicine (FRSM), the European EPMA National Representative in China, Regular Member of American Association for the Advancement of Science (AAAS), European Cooperation of Science and Technology (e-COST) grant evaluator, Associate Editors of BMC Genomics, BMC Medical Genomics, EPMA Journal, and Frontiers in Endocrinology, Executive Editor-in-Chief of Med One. He has\npublished 116 peer-reviewed research articles, 16 book chapters, 2 books, and 2 US patents. His current main research interest focuses on the studies of cancer proteomics and biomarkers, and the use of modern omics techniques and systems biology for PPPM in cancer, and on the development and use of 2DE-LC/MS for the large-scale study of human proteoforms.",institutionString:null,institution:{name:"Xiangya Hospital Central South University",country:{name:"China"}}},{id:"40482",title:null,name:"Rizwan",middleName:null,surname:"Ahmad",slug:"rizwan-ahmad",fullName:"Rizwan Ahmad",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/40482/images/system/40482.jpeg",biography:"Dr. Rizwan Ahmad is a University Professor and Coordinator, Quality and Development, College of Medicine, Imam Abdulrahman bin Faisal University, Saudi Arabia. Previously, he was Associate Professor of Human Function, Oman Medical College, Oman, and SBS University, Dehradun. Dr. Ahmad completed his education at Aligarh Muslim University, Aligarh. He has published several articles in peer-reviewed journals, chapters, and edited books. His area of specialization is free radical biochemistry and autoimmune diseases.",institutionString:"Imam Abdulrahman Bin Faisal University",institution:{name:"Imam Abdulrahman Bin Faisal University",country:{name:"Saudi Arabia"}}},{id:"41865",title:"Prof.",name:"Farid A.",middleName:null,surname:"Badria",slug:"farid-a.-badria",fullName:"Farid A. Badria",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/41865/images/system/41865.jpg",biography:"Farid A. Badria, Ph.D., is the recipient of several awards, including The World Academy of Sciences (TWAS) Prize for Public Understanding of Science; the World Intellectual Property Organization (WIPO) Gold Medal for best invention; Outstanding Arab Scholar, Kuwait; and the Khwarizmi International Award, Iran. He has 250 publications, 12 books, 20 patents, and several marketed pharmaceutical products to his credit. He continues to lead research projects on developing new therapies for liver, skin disorders, and cancer. Dr. Badria was listed among the world’s top 2% of scientists in medicinal and biomolecular chemistry in 2019 and 2020. He is a member of the Arab Development Fund, Kuwait; International Cell Research Organization–United Nations Educational, Scientific and Cultural Organization (ICRO–UNESCO), Chile; and UNESCO Biotechnology France",institutionString:"Mansoura University",institution:{name:"Mansoura University",country:{name:"Egypt"}}},{id:"329385",title:"Dr.",name:"Rajesh K.",middleName:"Kumar",surname:"Singh",slug:"rajesh-k.-singh",fullName:"Rajesh K. Singh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/329385/images/system/329385.png",biography:"Dr. Singh received a BPharm (2003) and MPharm (2005) from Panjab University, Chandigarh, India, and a Ph.D. (2013) from Punjab Technical University (PTU), Jalandhar, India. He has more than sixteen years of teaching experience and has supervised numerous postgraduate and Ph.D. students. He has to his credit more than seventy papers in SCI- and SCOPUS-indexed journals, fifty-five conference proceedings, four books, six Best Paper Awards, and five projects from different government agencies. He is currently an editorial board member of eight international journals and a reviewer for more than fifty scientific journals. He received Top Reviewer and Excellent Peer Reviewer Awards from Publons in 2016 and 2017, respectively. He is also on the panel of The International Reviewer for reviewing research proposals for grants from the Royal Society. He also serves as a Publons Academy mentor and Bentham brand ambassador.",institutionString:"Punjab Technical University",institution:{name:"Punjab Technical University",country:{name:"India"}}},{id:"142388",title:"Dr.",name:"Thiago",middleName:"Gomes",surname:"Gomes Heck",slug:"thiago-gomes-heck",fullName:"Thiago Gomes Heck",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/142388/images/7259_n.jpg",biography:null,institutionString:null,institution:{name:"Universidade Regional do Noroeste do Estado do Rio Grande do Sul",country:{name:"Brazil"}}},{id:"336273",title:"Assistant Prof.",name:"Janja",middleName:null,surname:"Zupan",slug:"janja-zupan",fullName:"Janja Zupan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/336273/images/14853_n.jpeg",biography:"Janja Zupan graduated in 2005 at the Department of Clinical Biochemistry (superviser prof. dr. Janja Marc) in the field of genetics of osteoporosis. Since November 2009 she is working as a Teaching Assistant at the Faculty of Pharmacy, Department of Clinical Biochemistry. In 2011 she completed part of her research and PhD work at Institute of Genetics and Molecular Medicine, University of Edinburgh. She finished her PhD entitled The influence of the proinflammatory cytokines on the RANK/RANKL/OPG in bone tissue of osteoporotic and osteoarthritic patients in 2012. From 2014-2016 she worked at the Institute of Biomedical Sciences, University of Aberdeen as a postdoctoral research fellow on UK Arthritis research project where she gained knowledge in mesenchymal stem cells and regenerative medicine. She returned back to University of Ljubljana, Faculty of Pharmacy in 2016. She is currently leading project entitled Mesenchymal stem cells-the keepers of tissue endogenous regenerative capacity facing up to aging of the musculoskeletal system funded by Slovenian Research Agency.",institutionString:null,institution:{name:"University of Ljubljana",country:{name:"Slovenia"}}},{id:"357453",title:"Dr.",name:"Radheshyam",middleName:null,surname:"Maurya",slug:"radheshyam-maurya",fullName:"Radheshyam Maurya",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/357453/images/16535_n.jpg",biography:null,institutionString:null,institution:{name:"University of Hyderabad",country:{name:"India"}}},{id:"418340",title:"Dr.",name:"Jyotirmoi",middleName:null,surname:"Aich",slug:"jyotirmoi-aich",fullName:"Jyotirmoi Aich",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000038Ugi5QAC/Profile_Picture_2022-04-15T07:48:28.png",biography:"Biotechnologist with 15 years of research including 6 years of teaching experience. Demonstrated record of scientific achievements through consistent publication record (H index = 13, with 874 citations) in high impact journals such as Nature Communications, Oncotarget, Annals of Oncology, PNAS, and AJRCCM, etc. Strong research professional with a post-doctorate from ACTREC where I gained experimental oncology experience in clinical settings and a doctorate from IGIB where I gained expertise in asthma pathophysiology. A well-trained biotechnologist with diverse experience on the bench across different research themes ranging from asthma to cancer and other infectious diseases. An individual with a strong commitment and innovative mindset. 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In 2016, he joined Kafkas University, Faculty of Veterinary Medicine, Department of Physiology as an assistant professor. Dr. Gelen has been engaged in various academic activities at Kafkas University since 2016. There he completed 5 projects and has 3 ongoing projects. He has 60 articles published in scientific journals and 20 poster presentations in scientific congresses. His research interests include physiology, endocrine system, cancer, diabetes, cardiovascular system diseases, and isolated organ bath system studies.",institutionString:"Kafkas University",institution:{name:"Kafkas University",country:{name:"Turkey"}}},{id:"418963",title:"Dr.",name:"Augustine Ododo",middleName:"Augustine",surname:"Osagie",slug:"augustine-ododo-osagie",fullName:"Augustine Ododo Osagie",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/418963/images/16900_n.jpg",biography:"Born into the family of Osagie, a prince of the Benin Kingdom. 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He owns the patent for herbal preparation and producing, and for the supercritical fluid-treated needle. Dr. Hu has published three books, 12 book chapters, and more than 30 papers in reputed journals, besides serving as an editorial board member of repute.",institutionString:"Kaohsiung Chang Gung Memorial Hospital",institution:{name:"Kaohsiung Chang Gung Memorial Hospital",country:{name:"Taiwan"}}},{id:"298472",title:"Prof.",name:"Andrey V.",middleName:null,surname:"Grechko",slug:"andrey-v.-grechko",fullName:"Andrey V. Grechko",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/298472/images/system/298472.png",biography:"Andrey Vyacheslavovich Grechko, Ph.D., Professor, is a Corresponding Member of the Russian Academy of Sciences. He graduated from the Semashko Moscow Medical Institute (Semashko National Research Institute of Public Health) with a degree in Medicine (1998), the Clinical Department of Dermatovenerology (2000), and received a second higher education in Psychology (2009). Professor A.V. Grechko held the position of Сhief Physician of the Central Clinical Hospital in Moscow. He worked as a professor at the faculty and was engaged in scientific research at the Medical University. Starting in 2013, he has been the initiator of the creation of the Federal Scientific and Clinical Center for Intensive Care and Rehabilitology, Moscow, Russian Federation, where he also serves as Director since 2015. He has many years of experience in research and teaching in various fields of medicine, is an author/co-author of more than 200 scientific publications, 13 patents, 15 medical books/chapters, including Chapter in Book «Metabolomics», IntechOpen, 2020 «Metabolomic Discovery of Microbiota Dysfunction as the Cause of Pathology».",institutionString:"Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology",institution:null},{id:"199461",title:"Prof.",name:"Natalia V.",middleName:null,surname:"Beloborodova",slug:"natalia-v.-beloborodova",fullName:"Natalia V. Beloborodova",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/199461/images/system/199461.jpg",biography:'Natalia Vladimirovna Beloborodova was educated at the Pirogov Russian National Research Medical University, with a degree in pediatrics in 1980, a Ph.D. in 1987, and a specialization in Clinical Microbiology from First Moscow State Medical University in 2004. She has been a Professor since 1996. Currently, she is the Head of the Laboratory of Metabolism, a division of the Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology, Moscow, Russian Federation. N.V. Beloborodova has many years of clinical experience in the field of intensive care and surgery. She studies infectious complications and sepsis. She initiated a series of interdisciplinary clinical and experimental studies based on the concept of integrating human metabolism and its microbiota. Her scientific achievements are widely known: she is the recipient of the Marie E. Coates Award \\"Best lecturer-scientist\\" Gustafsson Fund, Karolinska Institutes, Stockholm, Sweden, and the International Sepsis Forum Award, Pasteur Institute, Paris, France (2014), etc. Professor N.V. Beloborodova wrote 210 papers, five books, 10 chapters and has edited four books.',institutionString:"Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology",institution:null},{id:"354260",title:"Ph.D.",name:"Tércio Elyan",middleName:"Azevedo",surname:"Azevedo Martins",slug:"tercio-elyan-azevedo-martins",fullName:"Tércio Elyan Azevedo Martins",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/354260/images/16241_n.jpg",biography:"Graduated in Pharmacy from the Federal University of Ceará with the modality in Industrial Pharmacy, Specialist in Production and Control of Medicines from the University of São Paulo (USP), Master in Pharmaceuticals and Medicines from the University of São Paulo (USP) and Doctor of Science in the program of Pharmaceuticals and Medicines by the University of São Paulo. Professor at Universidade Paulista (UNIP) in the areas of chemistry, cosmetology and trichology. Assistant Coordinator of the Higher Course in Aesthetic and Cosmetic Technology at Universidade Paulista Campus Chácara Santo Antônio. Experience in the Pharmacy area, with emphasis on Pharmacotechnics, Pharmaceutical Technology, Research and Development of Cosmetics, acting mainly on topics such as cosmetology, antioxidant activity, aesthetics, photoprotection, cyclodextrin and thermal analysis.",institutionString:null,institution:{name:"University of Sao Paulo",country:{name:"Brazil"}}},{id:"334285",title:"Ph.D. Student",name:"Sameer",middleName:"Kumar",surname:"Jagirdar",slug:"sameer-jagirdar",fullName:"Sameer Jagirdar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/334285/images/14691_n.jpg",biography:"I\\'m a graduate student at the center for biosystems science and engineering at the Indian Institute of Science, Bangalore, India. 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He has experience teaching DPharm, Pharm.D, BPharm, and MPharm students. He has more than five publications in reputed journals to his credit. Dr. Faheem’s research area is the development and characterization of nanoformulation for the delivery of drugs to various organs.",institutionString:"Integral University",institution:{name:"Integral University",country:{name:"India"}}},{id:"329795",title:"Dr.",name:"Mohd Aftab",middleName:"Aftab",surname:"Siddiqui",slug:"mohd-aftab-siddiqui",fullName:"Mohd Aftab Siddiqui",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/329795/images/system/329795.png",biography:"Dr. Mohd Aftab Siddiqui is an assistant professor in the Faculty of Pharmacy, Integral University, Lucknow, India, where he obtained a Ph.D. in Pharmacology in 2020. He also obtained a BPharm and MPharm from the same university in 2013 and 2015, respectively. 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