\r\n\t1. Emphasizing the unique power of the molecular docking method in new drug discovery; \r\n\t2. Demonstration of how the molecular docking technique has led to the discovery of new molecules in cancer therapy, proteasome, and STAT3 inhibition, and the treatment of Alzheimer's disease; \r\n\t3. Underlining the importance of molecular docking-based modeling methods in the various branches of biotechnology
\r\n
\r\n\tWe hope that this book will be a common point where researchers working in the fields of life sciences and drug development will eventually meet.
",isbn:"978-1-80356-468-5",printIsbn:"978-1-80356-467-8",pdfIsbn:"978-1-80356-469-2",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,isSalesforceBook:!1,isNomenclature:!1,hash:"8c918a1973786c7059752b28601f1329",bookSignature:"Dr. Erman Salih Istifli",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11451.jpg",keywords:"Protein-Ligand Interaction, Lead Discovery, Molecular Recognition, Enzyme-Ligand Interaction, Mutant Enzymes, Alanine Screening, Proteasome Inhibitors, Signal Transducers, Transcription Activators (STATs), DNA Recognition Motifs, Neoplastic Cells, Amyloid-Beta Proteins",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"March 3rd 2022",dateEndSecondStepPublish:"May 4th 2022",dateEndThirdStepPublish:"July 3rd 2022",dateEndFourthStepPublish:"September 21st 2022",dateEndFifthStepPublish:"November 20th 2022",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"2 months",secondStepPassed:!0,areRegistrationsClosed:!0,currentStepOfPublishingProcess:4,editedByType:null,kuFlag:!1,biosketch:"A multidisciplinary researcher working in the fields of cytogenetics, molecular genetics, and bioinformatics-based molecular modeling (currently on the structural biology of COVID-19 and the treatment of Alzheimer’s disease). 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1. Introduction
Synthetic pesticides have been used in Africa since more than eight decades. They were probably introduced in the continent by colonial masters. From a historical point of view, the Public Health Act of the British government legislation, to protect human beings and regulate the use of pesticides by farmers in Kenya, was enacted in 1921 [1]. From that period till date, African countries continue to import pesticides from more advanced economies, mainly from European countries and recently from China.
The FAO statistical (FAOSTAT) database estimated that Africa have imported in 2016 pesticides for a value of 1590160.326 USD [2]. However, since few years, pesticides importation from China is constantly growing.
According to the export statistics from China Customs, export volume of pesticides (under HS code 29 and 38) during January to November in 2015, African markets represented 13.9% of the total export of pesticides from China and concerned 44 countries. Top 10 countries by export value are Nigeria, South Africa, Ghana, Ivory Coast, Egypt, Kenya, Cameroon, Tanzania, Ethiopia, and Guinea. The amount of export value for these top 10 countries constitutes 85.9% of the total export value to Africa from China, as shown in Figure 1 [3].
Figure 1.
Top 10 of pesticides export in Africa by export values (adapted from Agronews).
Thousands of pesticides are imported, but the top 10 of most imported formulation products and active ingredients can be seen in Table 1.
Formulation products
Export value (million USD)
Export volume (000 tons)
Glyphosate IPA 41% SL
93.82
50.82
Paraquat 200 g/L SL
62.53
25.97
Glyphosate 30%
20.07
10.44
Lambda-cyhalothrin 25 g/L EC
16.97
5.68
Mancozeb 80% WP
16.69
5.08
Glyphosate-monoammonium 75.7% SG
16.33
4.84
2,4-D-dimethylammonium 720 g/L SL
14.78
7.29
Mancozeb 64% + Metalaxyl 8% WP
11.61
1.80
Atrazine 80% WP
10.19
3. 13
Imidacloprid 20% SL
8. 13
1.91
Total
271.12
111.69
Table 1.
Top 10 of most imported formulation products and active ingredients (adapted from Agronews)
Top 10 of most imported pesticides are mostly herbicides, followed by next 10 others products formulations which are mainly insecticides (chlorpyrifos, dichlorvos, dimethoate, abamectin, and cypermethrin).
It should be noted that in almost all countries, before their importation, pesticide products have to be homologated and authorized. Information are also provided to users on the purposes to which the products should be used, the dosage, their toxicological classes, first aid action to be taken in case of exposure, and even antidote in case of swallowed. Despite these precautions, Pouokam et al. [4] have reported several misuses in many countries and in particular in Cameroon.
2. Uses and misuses of agricultural pesticides in Africa
Pesticide homologation procedures are established in all African countries. Procedures differ from one country to another, and the majority of pesticides formulations are homologated for uses in agriculture. In this chapter, we recall some key information concerning the number of pesticides formulations in distribution in the top 10 pesticides importers as indicated above.
In Cameroon, the official database from the Ministry of Agriculture counted up to 610 [4]. de Vos et al. reported 500 pesticide formulations used in South Africa Republic [5]. In 2011, the volume of imported pesticides in Ghana was 20,747 tons (9216 tons of insecticides, 8986 tons of herbicides, 2545 tons of fungicides) [6]. Ivory Coast and 13 other countries of the Permanent Interstate committee for Drought Control in the Sahel (CILLS), namely, Benin, Burkina Faso, Cap-Vert, Guinea, Gambie, Guinee-Bissau, Mali, Mauritania, Niger, Senegal, Tchad, and Togo, had adopted a common homologation procedures. The actual homologated list contains 438 pesticides formulations [7]. In 2016, Egypt consumed up to 10,600 metric tons of pesticides formulations [8]. Between July 2013 and June 2014, a total of 1182 different types of pesticides were registered in Tanzania, of which 11.2% were provisionally registered [9]. In 2017, 117 pesticide formulations were found to be homologated for used in Ethiopia, among which were 68 insecticides, 45 herbicides, and 4 fungicides [10].
Major uses of pesticides include agriculture, livestock development, and disease vectors control. Choice of pesticides depends on farmers’ perception of its efficacy on pests, type and intensity of pests, crops growth stage and availability of pests, crops growth, and the availability of pesticide [11].
Supply channels of pesticides are both formal and informal and include:
Authorized retail outlets of agricultural supply companies
Government extension services
Small-scale informal traders operating via local shops
Itinerant peddlers visiting villages and weekly markets
Bulk supplies from general markets in larger cities
A lot of misuses have also been reported in field farms because of (i) absence of clear instructions, (ii) illiteracy of farmers, (iii) lack of knowledge on risks from bad uses, (iv) uses of pesticides on crops for which the product was not homologated, and (v) difficulties to properly prepare the solution to be used, and poor respect of dosage [12].
In Benin Republic, previous studies, for example, revealed that farmers have been found to use insecticides registered for cotton protection on vegetables [12]. Moreover, Pouokam et al. observed the reuses of pesticides empty containers for drinking water and traditional wine. Other containers are washed and rinsed in rivers were populations fetch water for domestic uses [4].
Pesticide applications also vary with the type of crops and the type of equipment used, most farmers used knapsack and therefore carry the equipment on their back; others used atomizer, especially cocoa farmers. Because they did respect wind direction, they often received pesticides vapor in their eyes and bodies part.
A detail analysis of all these practices gives insight on potential risk factors of pesticide exposures both for workers and nearby populations.
3. Use of predictive pesticides exposure models for occupational and para-occupational scenarios
Practice of agriculture in Africa is dominated by small farmers and family farmers whose one characteristic is that they operate in the informal sector. They are not registered and most of the time remains unknown by local authorities. This absence of clear statute for agricultural workers makes it difficult to organized and regulate the sector. Another consequence is the poor identification of exposure and poisoning cases.
Naveen Kumar et al. defined pesticides exposures as the contact of the pesticides with a surface or an organism. For a human, it means getting pesticides in or on the body [13].
Occupational and para-occupational exposures to agricultural pesticides in Africa remain as key concern that are unfortunately poorly addressed. Occupational exposure occurred in work places and concerned workers, while the definition of para-occupational exposure refers to exposure of people who may not formally work on farms but live on or near sprayed areas or participate in unpaid farmwork [14].
Several studies have found that farmers in their majority did not respect good practices recommended by international agencies and local authorities. Exposure to pesticides therefore often occurs while preparing the spray solutions, loading in the spray tank, and applying the pesticide [15]. Circumstances of poisoning vary: 27% during spraying, 20% by ingestion (drinking, food contaminated by hands that have been used to manipulate pesticides), 13% occurred at home, 7% in the kitchen, and 3% during fishing [4].
Occupational exposure concerned up to 30% of poisoning cases. Common occupational risk factors include (i) absence of personal protective equipment, (ii) spraying in a direction opposite to wind, (iii) aerial sprayed, (iv) pesticides pouring on the skin, (v) pesticides entering in the eyes, noise, and mouth, and (vi) respect of the indicated dosage.
Putting together these risk factors can help develop an occupational and para-occupational exposure model, in order to estimate exposure circumstances for a rapid and adequate case management.
The gravity and the seriousness of exposures will also depend on the toxicological class of the pesticides, the quantity of pesticides exposed, the frequency, and other vulnerability factors.
In many country of the continent, diseases causes by pesticides are not recognized as professional diseases and include in security health assessment measures to be carried out at workplaces, especially where agriculture mainly depends on family farmers and small exploitations.
There are many different pesticide exposure scenarios. Operator exposure monitoring is of great concern, because it is known that operators receive more pesticide exposure than any other type of worker due to their close proximity and amount of pesticide handled.
Models give the possibilities to estimate the exposure to an active substance or to rank exposure of one pesticide to others used in similar conditions. Model development required a clear formulation of the problem, as well as proper selection of key variables and indicators. First pesticide exposures models were developed around 1980, and since then, these models had been constantly refined. It should be recalled that models proposed are only as accurate as the input values fed into them. These models in some extend are complementary as they deal with various aspect and routes of pesticides exposures. Table 2 is a summary of some exposure models involving human monitoring.
Summary of some pesticides exposure models involving human monitoring (adapted from [16]).
Assumptions and parameters used to build these models are often based on pesticide uses in European and North American models, which do not properly correspond to various exposure scenarios found in Africa. Agricultural pesticides in Africa is mostly used in family farming, and some related features of exposures remains to be taken into account to fit existing models to ongoing practices on the continent.
4. Farmers perceptions and experience of harmful effects of pesticides
Pesticides toxicity varies from one molecule to another. Classification by the World Health Organization (WHO) is done according to pesticides lethal dose 50 (LD50). LD50 varies from slightly toxic (LD50 > 5000 mg/kg) to extremely toxic (LD50 < 50 mg/kg). Depending on circumstances, exposure can be done through breathing, eating, or drinking or by contact with the skin or eyes. During an investigation by Cheke et al., a medical examination was done on farmers in Ekiti State, Nigeria, after taking their perceptions on any harmful effects they had experienced [17]. More than 91% of farmers reported to had suffered from pesticide-related health symptoms during or after applications. Symptoms were nausea, headache, vomiting, eye irritation, and skin problems, as shown in Figure 2.
Figure 2.
Pesticide health symptoms experienced by farmers.
In 2011, Mokhele determined the perceptions and awareness of farmworkers in Lesotho in South African Republic regarding the use of pesticides and the potential effects on their health. A total of 30 farmers from 6 farms participated [18]. The majority (85%) of farmworkers terminated their educational studies at the end of primary school. About 93% of farmworkers had received no training in the use of pesticides. A total of 52% of the farmworkers never wore rubber gloves when using or handling pesticides. All farmworkers in this study used a knapsack sprayer.
In the East African Rift (Ethiopia, Kenya, Tanzania, Uganda), Jacob de Boer et al. review literature about import, disposal, and health impacts of pesticides. They found out that in Ethiopia, few cases of poisoning have been reported [19]. Documented cases reported 81 pest control workers who were exposed to organochlorine pesticides (OCPs) (chlorpyrifos and profenofos) had lower cholinesterase levels after pesticide spraying. In Tanzania, data revealed that more than 50% of farmers have experienced headaches, excessive salivation, nausea, vomiting, and skin or eye irritation. Over 40% experienced dizziness, blurred vision, sleeplessness, and breathing difficulties, and over 20% reported tremors, diarrhea, chest pain, pain when urinating, fever, wheezing, or nosebleed.
In Kenya, Tsimbiri et al. testified that the main health impact of pesticides on residents and workers at Lake Naivasha in Kenya were headache and miserableness, followed by respiratory symptoms [20].
Apart from occupational and para-occupational exposures, pesticide dietary intake appears to be an overneglected issue. Even when good agricultural practices are followed, it is recognized that residues of pesticides remain on treated foods and agricultural products. The level of residues can be much higher in scenarios where pesticide misuses are numerous like in Africa.
5. Levels of pesticide residues in some highly consumed foods
In most African countries, pesticide residues are not of concerns in agricultural products sold at local markets, on the contrary to export products, which raises more attention. Residues on produce resulting from the inappropriate use of pesticides are however one of the most important food safety concerns. Table 3 gives a snapshot of pesticide residue levels in foods from the 10 countries identified as main importers.
Pesticide residue levels in some of highly consumed food items.
NI: Not indicated
Table 3 shows just a quick example of the type of pesticide residues that can be found in foods sold in market places of the continent. In all countries cited in the table, we have not been able to find any database of pesticide residues in foods. We focus on top 10 African countries importing pesticides from China. Others pesticide residues have been detected in African food products during their export into the European markets and notified on the Rapid Alert System for Food and Feed (RASFF) portal; an example of ethephon is found in pineapples coming from South Africa. In that specific case, the level of ethephon detected was 7.2 mg/kg and was treated as serious [31].
Although herbicides are massively used, residues most often found in food items are insecticides. This can be due to their late uses in the production or during food conservation, especially in grains and cereals. Residues in most consumed foods are a clear indication of the level of exposure of the population.
Vegetables and grains appeared to be more frequently contaminated with residues.
In addition, multiple contaminations by 2–10 different pesticide active ingredients are also frequent, raising an issue of cocktail effects for a mixture of pesticides. Pesticides in combination may be far more dangerous and more serious threats for public health. Previous studies done on animal models showed various cocktail effects. Many chemical families of compound are involved specifically in synergy, addition, potentiation, and antagonism when combined.
Regulations of residues differ with countries; some countries had set their own maximum residue limits (MRLs) for certain pesticides in selected foods, and others have decided to adopt Codex alimentarius MRL. In both cases, actual levels of residues are found often to exceed national and/or international set MRLs.
6. Implications for pesticides dietary exposures and health risks
Pesticide residues refer to the pesticides that may remain on or in food after they are applied to food crops. Exposure of the general population to these residues most commonly occurs through consumption of treated commodities. Many food commodities are concerned with the exposure to several pesticide chemicals, especially staple foods, making it complex to estimate the dietary intake of residues.
To more accurately appreciate the health risk of pesticide residue intake, many approaches can be used. All of them are based on the assessment of level of residues in food commodities and the quantity of food consumed. Apart from being used as a starting point for estimating consumer exposures, MRLs are used also as reference points to decide misuses and as trade standards.
The use of food commodity MRL is a convenient way to assess the theoretical maximum daily intake (TMDI). This approach considered the set MRL as the contamination level assuming that farmers applied good agricultural practices. Unfortunately, from previous reading, we have seen that a huge number of farmers do not respect good agricultural practices, suggesting a higher level of residues and a higher risk for consumers.
In the example of Table 3, we observed that certain residue levels are higher than the set MRLs.
In South African Republic, Dalvie and London investigated the presence of pesticide residues in wheat produced and imported in the country and their health risks. Eight different pesticides were detected in total. The most frequently detected pesticides were mercaptothion (99%), permethrin (19%), and chlorpyrifos (17%). Nine (11%) samples exceeded the EU wheat. Risk index calculated was found to be lower in more than half of cases [32].
Determining exposure values based on pesticide residue levels and the food consumption is also possible using either the deterministic or probabilistic approach. The deterministic approach is simpler and based on single-point estimates for each variable in the model. On the other hands, probabilistic approach allows using all possible values for each variable to be taken into account, and each possible model outcome is weighted by the probability of its occurrence. Probabilistic is therefore advantageous in that all available data are used, the exposure estimate is presented as a distribution, and variability and uncertainty can be quantified. The deterministic approach may be used as a screening tool to identify problematic pesticides, followed by the probabilistic approach to see if the point estimate actually gives rise to concerns.
In Tanzania, Kimanya et al., in 2016, estimated deterministically the dietary pesticide exposure of population to three pesticides through consumption of fresh tomato. Pesticide levels were detected for permethrin (mean, 5.2899 mg/kg), chlorpyrifos (mean, 7.5281 mg/kg), and ridomil (mean, 2854.279 mg/kg) in 18% of samples. Health risk indices, determined as ratio of estimated daily intake to acceptable daily exposure, for chlorpyrifos, permethrin, and ridomil were greater than one, which implies that lifetime consumption of fresh tomatoes can pose health risk for chlorpyrifos, permethrin, and ridomil for population of Meru District [33].
7. Conclusion and perspectives
Synthetic pesticides have been used in Africa since they were introduced by colonial masters. Over the years, the quantities of pesticides used especially in agriculture have exponentially increased. These products are not manufactured in African countries, but mainly imported from developing economies. Products were previously imported from Europe but, since few years, are growingly coming from China. Herbicides and insecticides constitute the top 20 of imported pesticides.
Although pesticides are homologated before they can be used, their supply to farmers followed many channels among which some that are illegal, particularly when it comes to supply products in rural settings.
Moreover, a lot of misuses are still observed on the field. Good agricultural practices are not known by a great number of farmers and workers, increasing therefore risk factors of exposures and poisoning.
Farmers are frequently subjected to multiple exposures at workplace (inhalation, skin contact), while populations are exposed to pesticide residues found in the environment and accumulated in foods commodities. Estimating the level of human exposure for occupational and non-occupational scenarios remains a real challenge for risk assessors. A number of tools and techniques exist but do not fit to all situations, particularly in cases of misuses of pesticide applications. Predictive models have been designed to quickly capture and assess exposure cases, but these models remain to be improved to fit unusual practices by small farmers in rural areas of Africa.
Farmers are all aware of risks that pesticides can cause to their health; however, they remain reluctant in using protective equipment and to adopt preventive behavior. Most of them have reported to experience at workplaces symptoms of pesticide poisoning (eye irritation, skin irritation, nausea, headache, and vomiting).
Because of the absence of toxicovigilance systems, as well as surveillance and monitoring program, very few cases of pesticides poisoning have been documented. Epidemiological data are not known. Actual risk assessment is based on the estimation of dietary intake of pesticides. These calculations showed frequent contamination of food items by pesticide residues, especially insecticides. The level of residues is often higher than national and international maximum residue limits, suggesting real public health threats for the whole population. In addition, cocktail and cumulative effects of multiple residues remain to be investigated.
\n',keywords:"pesticide, exposure, poisoning, residues, misuses",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/65752.pdf",chapterXML:"https://mts.intechopen.com/source/xml/65752.xml",downloadPdfUrl:"/chapter/pdf-download/65752",previewPdfUrl:"/chapter/pdf-preview/65752",totalDownloads:1561,totalViews:51,totalCrossrefCites:4,totalDimensionsCites:8,totalAltmetricsMentions:3,impactScore:2,impactScorePercentile:77,impactScoreQuartile:4,hasAltmetrics:1,dateSubmitted:"September 21st 2018",dateReviewed:"January 20th 2019",datePrePublished:null,datePublished:"July 17th 2019",dateFinished:"February 20th 2019",readingETA:"0",abstract:"Pesticides are use in agriculture for their capacity to reduce pest and protect foods. Since their introduction in Africa by colonial masters, the use of these chemicals is constantly growing. Herbicides and insecticides are the two dominant categories. Although they are used in small quantities by farmers who own small exploitation, the frequency of their use, as well as overuses and misuses, constitutes serious factors of exposure and health risks. Farm workers are more vulnerable to occupational effects from pesticide inhalation and skin contacts. Failure to wear protective equipment and observe good agricultural practices explained health symptoms that are frequently experienced: eye and skin irritation, nausea, vomiting, and headache. Population is subject to chronic health effects due to repeated dietary intake of pesticides. Most consumed staple foods on the continent (cereals, vegetables, and fruits) have been found to be contaminated by one or multiple residues of pesticides. The level of residues is often higher than regulatory limits. Organization of surveillance programs to monitor concentration of pesticide residues remains inexistent in most countries, same for toxicovigilance systems to documented poisoning cases. Current data underline the need to carry out pesticide health risk assessment in order to appreciate the threats they pose for public health.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/65752",risUrl:"/chapter/ris/65752",book:{id:"8533",slug:"pesticides-use-and-misuse-and-their-impact-in-the-environment"},signatures:"Pouokam Guy Bertrand",authors:[{id:"276832",title:"Ph.D. Student",name:"Guy Bertrand",middleName:null,surname:"Pouokam",fullName:"Guy Bertrand Pouokam",slug:"guy-bertrand-pouokam",email:"guy.pouokam@noodlesonlus.org",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Uses and misuses of agricultural pesticides in Africa",level:"1"},{id:"sec_3",title:"3. Use of predictive pesticides exposure models for occupational and para-occupational scenarios",level:"1"},{id:"sec_4",title:"4. Farmers perceptions and experience of harmful effects of pesticides",level:"1"},{id:"sec_5",title:"5. Levels of pesticide residues in some highly consumed foods",level:"1"},{id:"sec_6",title:"6. Implications for pesticides dietary exposures and health risks",level:"1"},{id:"sec_7",title:"7. Conclusion and perspectives",level:"1"}],chapterReferences:[{id:"B1",body:'Wandiga SO. Use and distribution of organochlorine pesticides. The future in Africa. Pure and Applied Chemistry. 2001;73(7):1147-1155'},{id:"B2",body:'FAOSTAT: Pesticides Trade Database. Available from: http://www.fao.org/faostat/en/#data/RT [Accesed: December 17, 2018]'},{id:"B3",body:'Erwin X. Briefing on Export of Pesticides to Africa From China in 2015. Available from: http://news.agropages.com/News/NewsDetail---17241.htm [Accessed: November 11, 2018]'},{id:"B4",body:'Pouokam GB, Lemnyuy Album W, Ndikontar AS, MEH S. 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Cogent Food & Agriculture. 2016;2:1196808'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Pouokam Guy Bertrand",address:"guy.pouokam@noodlesonlus.org",affiliation:'
Nutrition and Food Safety and Wholesomeness, Cameroon
Laboratory of Biochemistry, Faculty of Medicine and Biomedical Sciences, University of Yaoundé 1, Cameroon
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1. Introduction
Chagas disease (CD), the parasitic infection caused by the kinetoplastid protozoan Trypanosoma cruzi, is also known as American trypanosomiasis, for the huge endemic areas in South and Central Americas [1], but autochthonous human [2, 3, 4] and domestic/wild animal [5, 6, 7, 8] cases were reported in the United States, and due to migration, it is already considered a public health problem on a global scale reaching different continents [9, 10, 11]. It is noteworthy that climate changes may promote the northward insect vector propagation [12], possibly generating new foci or endemic areas, and suitable climatic conditions may be available in African and Asian nations [13]. Besides the vector bloodmeal, congenital, blood transfusion and organ transplantation [14], CD may be transmitted orally via food and beverages contaminated by triatomine feces such as sugarcane and açai juices [15, 16] and even water, stored in/near domiciles in arid regions [15, 16], as the parasite is able to survive in such media [17].
It is alarming that 6–7 million people are estimated to have CD worldwide, with circa 173,000 new cases/year and over 75 million people are at risk. CD is the parasitic disease of highest mortality in Latin America as 9490 deaths were reported in 2019. Furthermore, the real prevalence is largely unknown as most chronic patients are asymptomatic and even symptomatic patients have poor access to health public system. CD is endemic in 21 countries in Central and Latin America where about 5.7 million people have CD and 25% of the population is at risk [18]. In 2020, it was estimated that there were 3.2 million infected people, which can reach 1.5% of the general population. In addition, about 70 million are at risk of infection [19]. The prevalence of CD is presumably vastly underestimated. In January 2020, a study carried out by the ArtScience Initiative for Health Promotion, carried out by Oswaldo Cruz Foundation (Fiocruz) and collaborating organizations, showed a CD seropositivity of 20% in a tested population of an endemic area [20]. It must be mentioned this study was not designed to access CD prevalence and was biased by the population intention to get diagnosis procedures.
CD represents economic losses in excess of $1.2 billion/year to endemic countries in South America, in addition to more than $7 billion a year at global levels [21], including treatment and loss of productivity. Since no proven effective and approved vaccines are available for this disease, chemotherapy represents the only therapeutic intervention, as well as an important way to control them.
CD etiological treatment is directed according to the phase and clinical presentation of the disease, which is mandatory in the acute phase, congenital cases, or reactivation due to immunosuppression. In the chronic phase, the trypanocidal treatment is indicated in children and adolescents, recent infection, and women of childbearing age [22].
2. Therapeutics
Although CD was discovered and is studied for over a century [14], the etiologic treatment is still based on solely two drugs (Figure 1): the nitrofuran derivative nifurtimox (NFX; Lampit®, Bayer; 5-nitrofuran(3-methyl-4-(5′-nitrofurfurylideneamine)tetrahydro-4H-1,4-tiazine-1,1-dioxide), and the 2-nitromidazole benznidazole (BZ; LAFEPE; N-benzyl-2-nitroimidazole-acetamide) [23]. Both NFX and BZ were shown to produce remarkable ultrastructural alterations in mammal cells and tissues [24, 25], which were apparently more pronounced in NFX-treated animals [26]. Therefore, experimental chemotherapy studies approaching parasites as T. cruzi should preferentially include ultrastructural analysis, in order to offer a subcellular compartmentation understanding to aid the antiparasitic agent mechanism(s) of action elucidation [27, 28] and ultimately leading to the understanding of cell death pathways involved [29].
Figure 1.
Molecular structures of the nitroheterocyclic drugs employed in the treatment of Chagas disease: the 2-nitroimidazole benznidazole (A) and the 5-nitrofuran nifurtimox (B).
The CD therapeutics remain unsatisfactory, as they are associated with adverse effects [30, 31, 32], affecting 84.8 and 95.2% of patients treated with BZ and NFX, respectively [33], which may be severe, leading to the irreversible suspension of therapy in CD, in ≈20% [34, 35], ≈30% [36, 37], 41.5% [38], and up to 50% of the cases [39, 40]. Treatment suspension using NFX was reported in 43.8% of patients [33]. In an early study based on small samples, NFX was reported to be associated to definitive treatment interruption in 75% of patients [38]. Nevertheless, treatment intolerance was reported at similar levels with the use of the two drugs, approached by the same team [34, 35], but adverse effects, including neuropsychiatric events, may be more frequently associated to NFX [33]. In addition, it was reported that among patients who had discontinued BZ treatment and were treated with NFX, 12.3% also developed adverse effects that required definitive discontinuation of therapy [39]. Nevertheless, NFX was reported to be safe as a second-line therapy in patients who discontinued BZ [41].
Most CD patients are not treated because of the insufficient diagnosis and low cure rates observed in chronically infected patients [42], although treatment may diminish the disease progression and cardiovascular events [43, 44]. In addition, the CD treatment accomplishes only a parasitological cure, and a clinical cure is hardly proved [43, 45]. Whereas the bona fide sterile cure or complete clearance of the infection is considered a “prerequisite” for new anti-T. cruzi drug candidates [46], it is usually not achieved in murine model [47, 48] or human infection as immunosuppression often leads to infection reactivation [49]. In this regard, T. cruzi amastigotes may persist in a dormant or quiescent form, which may protect the parasites from antiparasitic agents [50, 51].
As the dormancy state of T. cruzi amastigotes is associated to drug resistance [50, 51], it is desirable to develop drugs able to affect dormant parasites. The mechanisms that allow the establishment of persistence include the capacity to suppress the oxidative burst produced by phagocytes largely depending on iron-containing superoxide dismutases (FeSOD) and trypanothione-acting enzymes [52]. Thus the use of disulfiram (DSF) is of potential relevance since it can diminish glutathione levels [53, 54], and the DETC first derivative of DSF is an SOD inhibitor [55, 56]. Furthermore, DSF could target T. cruzi dormancy. Although the signal transduction pathways involved in this process were not completely elucidated, it is interesting that DSF is able to reverse HIV latency affecting PKC (protein kinase C), AKT (protein kinase B), PI3K (phosphoinositide 3-kinases), NF-kB (nuclear factor kappa-light-chain-enhancer of activated B cells) [57, 58], which also affect T. cruzi infection [59, 60] that leads to the activation of PI3K [61], whereas DSF promotes PI3K inhibition [62].
An important study [63] approached the persistent parasite elimination, but the use of higher BZ doses might pose higher risks for patients. In this regard, the polyamine and thiol synthesis Leishmania are associated to macrophage M2 phenotype, leading to parasite persistence [64].
2.1 Drug resistance
Besides considerable severe adverse effects, one of the greatest problems of CD therapeutics is the selection of resistant parasites, impairing its effectivity, therefore causing refractory cases. BZ and NFX resistance is readily developed in vitro and in vivo [47, 65], in the former case, via different mechanisms that can act in concert [66].
Despite significant time and resources investments by innumerous research institutions over the world, only a few therapeutic candidates advanced the pipeline to treat neglected diseases such as CD [67]. It is alarming that it usually takes over 10 years to develop new drugs, whereas resistant parasites are rapidly selected. Also, there are naturally resistant T. cruzi strains [68, 69, 70] that express a novel ABCG-like transporter [71]. Besides extrusion pumps, T. cruzi resistance may involve SOD and trypanothione (vide infra). Therefore, there is pressing demand for the development of novel effective therapies for CD.
3. Oxidative stress in Chagas disease
Oxidative stress is a central phenomenon involved in aging, cancer, transmissible or infectious diseases, including COVID-19 [72], nontransmissible chronic conditions, such as metabolic diseases, autoimmune and degenerative disorders, inflammation, metal poisoning, etc. [73, 74, 75], produced by the imbalance on the production/uptake of oxidant/antioxidant species [76].
A plethora of antioxidant defenses evolved in order to balance the redox homeostasis [76, 77]. Oxidant species such as superoxide (O2•−) and hydrogen peroxide (H2O2) are detoxified by SOD and catalase, respectively. Most cells rely also on the peptide glutathione (GSH), able to chelate reactive oxidant species (ROS) via cysteine sulfhydryl (SH) group and function as substrate for enzymes including GSH reductase and GSH peroxidase [78].
Although most of these processes are evolutionary conserved, some of the antioxidant defenses pathways differ between mammals and pathogens, therefore comprise potential chemotherapy targets. Contrary to mammals, GSH in trypanosomatid parasites mostly takes part in the adduct with the polyamine spermidine, forming N1,N8-bis(glutathionyl)spermidine (trypanothione, TSH), and therefore its expression depends on the GSH, TSH [79], and polyamine [80] metabolism pathways.
Metabolomics and gene expression studies [81] reveal the participation of both GSH and the spermidine synthesis pathway, indicating the participation of trypanothione, in the regulation of redox metabolism in trypanosomatids. GSH is very relevant not only in oxi-reductive homeostasis, as this molecule is also related to detoxification and resistance to different drugs/xenobiotics in tumor cells [82, 83] binding to drugs that are extruded via multidrug resistance transporters [84]. TSH binding to NFX and BZ is involved in the detoxication of these trypanocides [85, 86]. Therefore, glutathione/trypanothione can promote the action/reverse resistance to different drugs. T. cruzi parasites overexpressing trypanothione synthetase tolerated higher doses of BZ and NFX [87]. Conversely, the GSH biosynthesis inhibition using buthionine sulfoximine increases the efficacy of NFX and BZ upon T. cruzi in vitro [88] and NFX in vivo [89] as well as of stibogluconate on Leishmania (L.) donovani [90].
Interestingly, polyamine play pivotal roles in parasite cells [91, 92], including T. cruzi antioxidant defense [93], and its synthesis and transport pathways provide valuable chemotherapy targets [94, 95], including repositioned drugs [96].
Parasitic diseases such as CD are correlated to oxidative stress [97, 98], associated to triggered chronic inflammatory reactions [99, 100]. Endogenous oxidative stress may be produced by cell organelles, mainly mitochondria [101, 102]. The CD myocarditis is characterized by intense oxidative stress due both to inflammatory response associated to neutrophils and macrophages NADPH oxidase (Nox) activity and the macrophage superoxide produced by Nox2 is required for parasite control in early infection [103]. The mitochondrial ROS produced by cardiomyocytes plays a relevant role in intracellular oxidative stress and inflammation, causing myocardium tissue damage [104, 105, 106]. These events are not independent since mitochondrial ROS may trigger proinflammatory cytokines via NFkB and PARP/PAR pathways [107], and the mitochondrial MnSOD activity may revert much of the inflammatory foci and necrosis [105], and ineffective antioxidant defense is associated to oxidative stress [108]. Exosome or extracellular vesicles liberation may also contribute to inflammation and oxidative stress [107, 109]. The oxidative stress is also involved in neurodegeneration in both cardiac and gastrointestinal tissues [110]. The chronic oxidative stress in the nervous tissue is associated to cognitive deficit, which can be reversed by BZ treatment [111].
Thus, the use of adjuvant antioxidant agents may ameliorate the cardiac pathogenesis [107, 112, 113]. Interestingly, vitamin C, widely considered antioxidant, can at high concentrations also function as a prooxidant, undergoing pH-dependent autoxidation, leading to H2O2 formation [114, 115]. In CD models, ascorbic acid can also reduce parasitemia, promote BZ action, and enhance animal survival in murine infection [116, 117].
ROS production comprises a well-known microbicidal immune effector mechanism [118]; therefore parasite borne antioxidant systems are not only virulence factors [119]. Besides the parasiticidal activity, ROS may function as signaling molecules promoting parasite proliferation. As in the Paracelsus adage, “The dose makes the poison” (Latin: sola dosis facit venenum), ROS in mammalian cells may trigger different responses depending on concentration. Low ROS levels may have signal transduction roles, inducing responses such as activation, proliferation, and differentiation, whereas at higher levels such molecules are generally cytotoxic, leading to cell death [120]. Similarly, in T. cruzi, low ROS levels may signal for parasite invasion of host macrophages [121] and proliferation mainly in the acute phase [122], but high ROS levels culminate in programmed cell death, which may be inhibited by enhanced SOD expression [87]. Interestingly T. cruzi amastigotes undergo stress-induced proliferation [123].
4. Oxidative stress as a source of chemotherapy targets
Numerous therapeutic strategies exploit redox systems [124], including protozoal diseases [125], such as CD [126]. Therefore, antioxidant systems including SOD, trypanothione, and enzymes action on this glutathione-spermidine adduct (N1,N8-bis(glutathionyl)spermidine), such as trypanothione reductase, can comprise important chemotherapy targets [127]. Natural products such as the naphthoquinones
-/β-lapachones [128, 129, 130] and their derivatives [131, 132] have microbicidal activity against T. cruzi, among other pathogens [132]. Interestingly, β-lapachone derivatives were shown to cause mitochondrial dysfunction [131], damage [133], and autophagy, including mitophagy as well as apoptosis and necrosis [134]. In this regard, mitochondria comprise important therapeutical targets for cancer [135], aging [136], cardiovascular diseases [137], and degenerative diseases such as rheumatoid arthritis [138], Alzheimer’s disease [139], Parkinson’s disease [140], etc. Mitochondria are also promising target for antiparasitic [141, 142] and particularly antiprotozoal [143, 144, 145] therapeutic agents, specifically approached in trypanosomatids [146, 147, 148].
Up to 2% of the O2 reaching the mitochondrial matrix is converted to O2•− (superoxide anions) forming H2O2 via SOD [149]. Like mammalian cells, T. cruzi mitochondria are a source of ROS [150] producing superoxide. Therefore, the Mn-SOD is important for controlling oxidative stress in this redox organelle. Contrary to mammals, the trypanosomatid mitochondria present FeSOD [151] that can protect from O2•− produced by macrophages [152].
Because of the prooxidant effects of antiparasitic drugs [126, 153, 154, 155], ROS detoxifying systems may comprise valuable scape mechanisms from pharmaceutical intervention [156] and programmed cell death triggered by mitochondrial O2•− [157].
The prooxidant capacity of both NFX and BZ, particularly in the former, is due to redox cycling with the production of O2•− [126, 158, 159, 160]. Superoxide may be not produced by BZ in the parasite, but in the host cell [161]. Therefore, FeSOD is linked to BZ resistance in T. cruzi [66, 162, 163]. Proteome of BZ-resistant Trypanosoma cruzi revealed enhanced FeSOD activity [164]. BZ resistance was associated to decreased cytosolic SOD but enhanced mitochondrial MnSOD and tryparedoxin-1 [165]. The deletion of the sodb1 gene enhances Trypanosoma brucei susceptibility to BZ and NTX [166]. FeSOD is also implicated in drug resistance in L. (Viannia) braziliensis and L. (Leishmania) infantum [167, 168] Entamoeba histolytica [169]. Tryparedoxin peroxidase is also associated to antimony resistance in L. (V.) braziliensis [170]. In addition, SOD inhibition was reported to decrease parasitemia in T. cruzi murine infection [171].
Sirtuins are a highly conserved family of enzymes that deacetylate lysine residues on histone and non-histone proteins, using NAD+ as a cosubstrate, regulating cellular antioxidant/Redox mechanisms [172, 173]. It is noteworthy that SIRT3, 4, and 5 are found in the mitochondrial matrix [174]. As cardiomyocyte mitochondrial dysfunction plays a central role in chagasic myocarditis (vide supra), the activation of sirtuins such as SIRT1 by agonists including resveratrol may enhance antioxidant defenses [175], and SIRT3 activates MnSOD, scavenging ROS [176]. Nevertheless, the sirtuin TcSir2rp3 was shown to increase T. cruzi resistance to BZ and NTX for overexpressing TcFeSOD-A activities [177].
Selenium and selenium-containing compounds show beneficial effects both in murine [178, 179, 180] and human T. cruzi infection [181, 182], therefore comprise promising coadjuvant therapies for CD [183, 184, 185], although selenium was previously reported to increase tissue parasitism [186].
This activity maybe largely dependent on redox regulation as this inflammatory infection is associated with intense oxidative stress, and selenium may be antioxidant [187] and anti-inflammatory [188], as well as catalyze hydrogen peroxide (H2O2) reduction [189], therefore possibly diminishing the oxidative stress in infected cardiomyocytes, by impairing the Fenton reaction in the presence of iron.
5. Repositioning and combining drugs
The combination of different drugs may pose the advantage of supra-additive effects, which may be synergistic, in parasite models such as T. cruzi [190], Plasmodium falciparum, Trypanosoma rhodesiense [191]. The identification of synergistic combinations is relevant since they tend to present higher selective indices [192, 193], consequently, avoiding side effects and potentially permitting development of antiparasitic agents used at lower concentrations.
The identification of drug combinations with multiple targets can lead to the use of novel multitarget mechanisms able to cope with the challenge of multigenic diseases [194] and/or chronic infections with complex pathophysiology. It is noteworthy that the pharmaceutical properties of the combination may be absent in the components alone [195], generating the innovative concept or science field termed polypharmacology with numerous applications on drug repurposing [196] and CD [197]. As the philosopher Aristotle (384–322 B.C.) stated: “The whole is greater than the sum of its parts.”1
Furthermore, drug combinations are largely employed for preventing drug resistance [198, 199, 200, 201, 202, 203, 204]. However, this strategy is not constantly successful as the reports of resistance to the sulfadoxine-pyrimethamine combination began in the same year this antimalarial regimen entered the clinic [205]. Similarly, the discovery of artemisinin (ART) costed Youyou Tu over 30 years of hard work [206] and was worthy a Nobel Prize, but P. falciparum resistance to the drug was detected after about 10 years of use [207]. The antimalarial combination therapies based on the use of ART were considered key to the elimination of malaria [208], but in the very same year [209, 210] and even earlier [211], the arteminisin derivatives combination therapy failures were reported. In the case of CD, the problem may be even more upsetting as natural resistance isolates are arising, particularly in the Amazon region (vide supra). Thus, effective strategies to prevent different mechanisms of drug resistance to arise are immediately needed.
Approaching repositioned drugs with available pharmacokinetic and toxicological properties can shorten the long and expensive path between in vitro trials and new drugs. While the period between drug discovery and approval can be 12–16 years at a cost of US$1–2 billion, repositioned drugs can enter the clinic in ½ the time, at circa 1/3 the cost [212], with much higher success rates [213].
Drug repositioning maybe a promising approach in CD [214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227]. Similarly, drug combinations may be instrumental in CD [197, 228, 229, 230, 231, 232, 233], and both strategies may be employed and associated [214, 234, 235, 236]. Furthermore, drug combinations can increase success of drug repositioning [237]. In addition, it was accurately hypothesized that the combined use of repurposed drugs with BZ could be more efficacious than BZ alone [238].
5.1 Repositioning disulfiram
Disulfiram (DS, 1,1′-disulfanediylbis(N,N-diethylmethanethioamide) also termed tetraethylthiuram disulfide; CAS no. 97-77-8; Molecular Formula: C10H20N2S4), a repositioned drug used in alcoholism and marketed as Antabuse® (Figure 2), was approved for medical use over 70 years ago and is widely used since then [239, 240].
Figure 2.
Molecular structures of disulfiram (A) and sodium diethyldithiocarbamate (B).
At the very beginning, the discovery of thiocarbamates and its derivatives was serendipitous and showed clear signs of versatile perspectives that unequivocally culminated in the present promising repurposing strategies for both pharmaceutical and industrial applications [241, 242].
In the 1930s and 1940s, dithiocarbamates such as dimethyldithiocarbamates and diethyldithiocarbamates were used as pesticides against fungal pathogens on different crops [243], besides biocides in household products [244].
The industry plant physician E. E. Williams in 1937 observed that workers using tetramethylthiuram monosulfide and disulfide to facilitate the rubber vulcanization became alcohol-intolerant and quit consuming alcoholic beverages. The DSF-induced alcohol aversion was described in 1948 [245]. At that time, DSF was approached as a vermicide and employed as an ointment to treat scabies.
Afterward, besides alcoholism, DSF started to be studied for heavy metal poisoning, cancer [246, 247, 248, 249], HIV [243, 250], as well as cocaine dependence, pathological gambling, and other psychiatric disorders [239] and other form of addiction, for example, the d-methamphetamine abuse [251]. Further tests are being performed focusing applications such as Alzheimer’s disease [252], Lyme disease and babesiosis [253], tuberculosis [254], non-tuberculous mycobacteria infections [255], giardiasis [256], amoebiasis [257], obesity [258] and to revert drug resistance in different types of cancer [259, 260, 261], tuberculosis [262] bacterial infections [263], mycosis [264], giardiasis [265], etc. The repositioning of low-cost drugs such as DS is considered a “salvation” for global healthcare system [266].
Sodium diethylcarbamodithioate (Figure 2) (DETC also known as sodium (diethylcarbamothioyl)sulfanide; CAS no. 148-18-5; Molecular Formula: C5H11NS2.Na) is the first derivative of DSF, involved in many of the biological activities of the latter.
Seemingly DETC is less toxic than aspirin [243], widely used, and well tolerated in humans [267] for decades being used up to 800 mg/twice/week, with no adverse effects [268]. DETC also known as Imuthiol or Dithiocarb was used as immunomodulator with good results on AIDS patients [269, 270] and was clinically employed in chronic bronchitis, rheumatoid arthritis, tuberculosis, and chronic infection [271].
In a seminal report on its antiparasitic activity, DETC was demonstrated to be leishmanicidal [272]. Afterward, novel delivery systems were developed to optimize the leishmanicidal activity of DETC [273, 274, 275]. In this regard, novel drug delivery systems are also developed for DSF [276]. The data obtained on Leishmania amazonensis motivated us to move to CD, employing the repositioned drug DSF combined to the drug of first choice BZ. Tests on NFX are in progress.
It is worth remembering that CD pathophysiology is associated with oxidative stress (vide supra), and both DSF [277] and DETC [278] can act as antioxidants. In addition, modulation of oxidative stress comprises a valuable tool in heart disease therapeutics [279]. In addition, DSF has antimutagenic properties [280].
5.2 Disulfiram combined to benznidazole in Chagas disease
Both DSF and DETC have antiparasitic activity on T. cruzi [281, 282], but the effectivity was not pronounced.
In our study, the DSF-BZ combination is promising since the antagonism of SOD activity can enhance oxidative stress in cancer cells [249] and T. cruzi [283]. In this regard, the antitumor activity of NTX is enhanced by SOD1 inhibition mediated by tetrathiomolybdate [284]. Both in vitro and in vivo experimental data confirmed the present assumption [Almeida-Silva et al., in press]. The SOD inhibition as well as TSH reaction by DSF/DETC can promote the intracellular accumulation of ROS leading to parasite death (Figure 3).
Figure 3.
Putative mechanisms of action of disulfiram (DSF) or diethyldithiocarbamate (DETC) in combination with trypanocides in T. cruzi infection. Benznidazole (BZ) and nifurtimox are toxic and produce adverse reactions (1), which are ameliorated via detoxification mediated by DSF or DETC (2). The anti-T. cruzi agents trigger the formation of reactive oxygen species (ROS, 3) via nitroanion radicals (RNO2•−) that give rise to superoxide (O2•−), that is detoxified by superoxide dismutase (SOD, 5), generating hydrogen peroxide (H2O2), which in the presence of iron can produce hydroxyl radicals (•OH) and hydroxide anions (−OH) via Fenton reaction. DETC inhibits SOD (4). ROS may be detoxified by reaction with sulfhydryl or thiol groups of trypanothione (N1,N8-bis(glutathionyl)spermidine, 6), and this adduct can be removed by reaction with thiols of DSF/DETC (7). The BZ molecules in the parasite cytoplasm are extruded from the cell via p-glycoproteins or MDR transporters (8), which are inhibited by DETC (9), presumably reversing resistance phenotypes.
CD etiological therapy is often associated to severe adverse effects caused by the highly toxic drugs (vide supra). In this sense, the present innovation involves the advantage of employing DSF/DETC with cytoprotective properties [243] in different cell types.
DSF/DETC have neuroprotective [285], hepatoprotective [277], and nephroprotective [286] and even radioprotective [287, 288] activity. These protective effects may be beneficial in the treatment of parasitic diseases, because in the treatment of experimental infection by T. rhodesiense, DSF has marked protective activity (disulfiram rescue) against the toxic effects of diaminodichloroplatin and preventing the death of the treated organism [289].
Thus, the development of low-toxicity therapies may be expected, as DSF may have a protective action against the toxic effects of drugs such as cyclophosphamide [290], ifosfamide [291], N-nitrosodimethylamine [292], isoniazid [293] and the toxicity of α-naphthylisothiocyanate [294], acetaminophen [295], pyrrolizidines [296], the lethal effects of hypoxia [297], ischemia [298], as well as lead [299], cadmium [300], mercury, and other heavy metals [301]. Thus, DSF combinations can enable the development of safe medicines. Regarding CD, the cardioprotective and antioxidant activities of DSF/DETC as well as atrial neuroprotection [302] are particularly desirable [303, 304, 305, 306]. In addition, DSF is effective as prophylactics in experimental colitis [307].
As drug resistance limits the successful CD therapy, the T. cruzi PgP expression has a pivotal role [308]. Therefore, it is relevant in the present approach that DSF/DETC inhibit PgP [261, 309, 310], causing the BZ accumulation within the parasite cytoplasm, enhancing trypanocidal activity, potentially reversing resistance phenotypes, such as MDR+ (Figure 3). Interestingly, the ABCC proteins from T. cruzi are involved in thiol transport [311]. In view of the glutathione-drug adduct transport by ABC transporters (vide supra), it is interesting that DSF reduces GSH levels [54] at least in part through the formation of complexes with its different derivatives [312].
DSF [313] affects the redox balance of the cell, to GSH oxidation [314], reducing GSH levels [54] at least in part through the formation of complexes with its different derivatives [312, 315]. DETC can also reduce the GSH/non-protein thiol levels, also leading to the reduction of glutathione peroxidase activities [53, 316].
The combinations tested here may also contribute to resistance reversal, also through DETC-mediated inhibition of Fe-dependent SOD, which is linked to resistance to BZ in T. cruzi [66, 162, 163].
Furthermore, DSF can be used against cancer cells targeting the ubiquitin-proteasome system [317], and the ubiquitin-proteasome pathway is a therapeutic target in T. cruzi [318].
In this way, the strategy based of combinations of the repositioned drugs proposed here can achieve effectiveness, with selectivity and, therefore, safety in the CD treatment and sheds new light on perspectives for new therapeutic strategies.
6. The clinical stage
Translational research in biomedical sciences translates basic research and experimental discoveries into health taking the route from benchtop to bedside. This important field has gained substantial attention and investments in the last two decades [319].
In order to reach a proof of concept on the effectivity of the DSF-BZ combination in human infection, a partnership was established gathering different units of Fiocruz. The present study comprises a translational approach that began with experiments in vitro, on the bench and now reaches the clinical stage at the Evandro Chagas National Institute of Infectious Diseases-Fiocruz, coordinated by the team of the Clinical Research Laboratory of Chagas Disease, with assistance of the Clinical Research platform. Therefore, the phase I/II clinical trial was elaborated (Figure 4) and published recently [320].
Figure 4.
Design of the clinical trial for testing the BZ-DSF combination. Reproduced from Ref. [320] (with permission).
7. Conclusions and future perspectives
The use of DSF/DETC combined to BZ in CD treatment comprises a potential innovative therapeutical tool, possibly overcoming adverse reactions and refractory cases. Since these repositioned drugs exert cytoprotective effects, reducing the adverse reactions of many drugs, safe combinations can be potentially identified, leading to the development of well-tolerated medication. Therefore, therapy interruption can be precluded, consequently increasing patient adherence. In addition, as DSF/DETC can inhibit p-glycoprotein activity as well as reduce GSH levels, two molecules involved in drug extrusion from MDR+ parasites, it is reasonable to suppose the combination could eventually revert/downmodulate natural/acquired resistance phenotypes. Thus, treatment may be effective even in refractory cases. We are now approaching the clinical response of chronic phase CD patients. A possible proof of concept may lead to the development of a safe and effective medication, with profound implications in treatment prognosis, presumably improving the quality of life of the patients.
Acknowledgments
This research was sponsored by grants from the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq grant no. 443886/2018-0 to RMS and CNPq grant no. 314717/2020 to MAVS), Fundação Carlos Chagas Filho de Amparo à Pesquisa do Rio de Janeiro (FAPERJ grant no. 211.167/2019 to RMS; FAPERJ grant no. 260475/2021 and 259286/2021 to MAVS and FAPERJ grant no. 204.388/2021 to AMSF) and Fundação Oswaldo Cruz (Fiocruz grant no. 6221125199 to MAVS).
\n',keywords:"drug combination, drug repositioning, translational medicine, Chagas disease, oxidative stress, Trypanosoma cruzi",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/81939.pdf",chapterXML:"https://mts.intechopen.com/source/xml/81939.xml",downloadPdfUrl:"/chapter/pdf-download/81939",previewPdfUrl:"/chapter/pdf-preview/81939",totalDownloads:22,totalViews:0,totalCrossrefCites:0,dateSubmitted:"February 14th 2022",dateReviewed:"March 3rd 2022",datePrePublished:"June 24th 2022",datePublished:null,dateFinished:"May 24th 2022",readingETA:"0",abstract:"Chagas disease, caused by the protozoan Trypanosoma cruzi, is a major neglected disease endemic to Latin America, associated to significant morbimortality comprising a remarkable socioeconomic problem mainly for low-income tropical populations. The present chapter focuses translational research on Chagas disease, approaching drug combinations and repositioning, particularly exploiting the parasite oxidative stress by prospecting prooxidant compounds combined with antagonists of antioxidant systems, for developing low-cost and safe therapies for this infection. The pertinent literature on protozoal parasitic diseases is reviewed as well as on repurposing disulfiram aiming the combination with the Chagas disease drug of choice benznidazole. Both disulfiram and its first derivative sodium diethyldithiocarbamate (DETC) are able not only to inhibit p-glycoprotein, possibly reverting resistance phenotypes, but also to reduce toxicity of numerous other drugs, heavy metals, etc. Therefore, this innovation, presently in clinical research, may furnish a novel therapeutic for T. cruzi infections overcoming the adverse effects and refractory cases that impair the effectiveness of Chagas disease treatment.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/81939",risUrl:"/chapter/ris/81939",signatures:"Marcos André Vannier-Santos, Ana Márcia Suarez-Fontes, Juliana Almeida-Silva, Alessandra Lifsitch Viçosa, Sandra Aurora Chavez Perez, Alejandro Marcel Hasslocher-Moreno, Gabriel Parreiras Estolano da Silveira, Luciana Fernandes Portela and Roberto Magalhães Saraiva",book:{id:"11377",type:"book",title:"Chagas Disease - From Cellular and Molecular Aspects of Trypanosoma cruzi-Host Interactions to the Clinical Intervention",subtitle:null,fullTitle:"Chagas Disease - From Cellular and Molecular Aspects of Trypanosoma cruzi-Host Interactions to the Clinical Intervention",slug:null,publishedDate:null,bookSignature:"Dr. Rubem Menna-Barreto",coverURL:"https://cdn.intechopen.com/books/images_new/11377.jpg",licenceType:"CC BY 3.0",editedByType:null,isbn:"978-1-80355-691-8",printIsbn:"978-1-80355-690-1",pdfIsbn:"978-1-80355-692-5",isAvailableForWebshopOrdering:!0,editors:[{id:"174902",title:"Dr.",name:"Rubem",middleName:null,surname:"Menna-Barreto",slug:"rubem-menna-barreto",fullName:"Rubem Menna-Barreto"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:null,sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Therapeutics",level:"1"},{id:"sec_2_2",title:"2.1 Drug resistance",level:"2"},{id:"sec_4",title:"3. Oxidative stress in Chagas disease",level:"1"},{id:"sec_5",title:"4. Oxidative stress as a source of chemotherapy targets",level:"1"},{id:"sec_6",title:"5. Repositioning and combining drugs",level:"1"},{id:"sec_6_2",title:"5.1 Repositioning disulfiram",level:"2"},{id:"sec_7_2",title:"5.2 Disulfiram combined to benznidazole in Chagas disease",level:"2"},{id:"sec_9",title:"6. The clinical stage",level:"1"},{id:"sec_10",title:"7. Conclusions and future perspectives",level:"1"},{id:"sec_11",title:"Acknowledgments",level:"1"}],chapterReferences:[{id:"B1",body:'Schmunis GA, Yadon ZE. Chagas disease: A Latin American health problem becoming a world health problem. Acta Tropica. 2010;115(1-2):14-21'},{id:"B2",body:'Montgomery SP, Parise ME, Dotson EM, Bialek SR. What do we know about Chagas disease in the United States? 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It often results in high productivity and requires large capital investments, low operating costs, and good safety conditions. The main topics that will be discussed in this chapter will include an introduction into the general features of open pit mining, ore body characteristics and configurations, stripping ratios and stripping overburden methods, mine elements and parameters, open pit operation cycle, pit slope angle, stability of mine slopes, types of highwall failures, mine closure and reclamation, and different variants of surface mining methods including opencast mining, mountainous mining, and artisan mining.",book:{id:"8620",slug:"mining-techniques-past-present-and-future",title:"Mining Techniques",fullTitle:"Mining Techniques - Past, Present and Future"},signatures:"Awwad H. Altiti, Rami O. Alrawashdeh and Hani M. Alnawafleh",authors:[{id:"313182",title:"Prof.",name:"Rami",middleName:null,surname:"Alrawashdeh",slug:"rami-alrawashdeh",fullName:"Rami Alrawashdeh"},{id:"313522",title:"Dr.",name:"Awwad",middleName:null,surname:"Altiti",slug:"awwad-altiti",fullName:"Awwad Altiti"},{id:"313523",title:"Prof.",name:"Hani",middleName:null,surname:"Alnawafleh",slug:"hani-alnawafleh",fullName:"Hani Alnawafleh"}]},{id:"64027",title:"Stages of a Integrated Geothermal Project",slug:"stages-of-a-integrated-geothermal-project",totalDownloads:4341,totalCrossrefCites:2,totalDimensionsCites:3,abstract:"A geothermal project constitutes two big stages: the exploration and the exploitation. Each one has a single task whose results allow defining the feasibility of a geothermal project, until achieving the construction and operation stage of the power generation plant. The first stage contains the area recognition, its limitation to the target, and elimination of external factors until defining a geothermal zone with characteristics to be commercially exploited. The main studies and analysis that can be applied during the exploration stage are listed, and the major indicator to continue with the project or suspend is the prefeasibility report. The major risks in the exploration stage are due to studies that are carried out on the surface; at this stage, the costs can be considered low. The main results of the exploration are the selection of sites to drill three or four initial wells. Each well provides a direct overview of the reservoir: depth, production thicknesses, thermodynamic parameters, and production characteristics. The drilling of three to four exploratory wells is recommended, as far as there is certainty of the feasibility of the project, and the development of the field begins with drilling of sufficient wells to feed the plant. In this stage, the cost increases, but the risks decrease.",book:{id:"7504",slug:"renewable-geothermal-energy-explorations",title:"Renewable Geothermal Energy Explorations",fullTitle:"Renewable Geothermal Energy Explorations"},signatures:"Alfonso Aragón-Aguilar, Georgina Izquierdo-Montalvo,\nDaniel Octavio Aragón-Gaspar and Denise N. Barreto-Rivera",authors:[{id:"258358",title:"Dr.",name:"Alfonso",middleName:null,surname:"Aragón-Aguilar",slug:"alfonso-aragon-aguilar",fullName:"Alfonso Aragón-Aguilar"}]},{id:"63059",title:"Generation, Evolution, and Characterization of Turbulence Coherent Structures",slug:"generation-evolution-and-characterization-of-turbulence-coherent-structures",totalDownloads:3618,totalCrossrefCites:3,totalDimensionsCites:4,abstract:"Turbulence stands as one of the most complicated and attractive physical phenomena. The accumulated knowledge has shown turbulent flow to be composed of islands of vortices and uniform-momentum regions, which are coherent in both time and space. Research has been concentrated on these structures, their generation, evolution, and interaction with the mean flow. Different theories and conceptual models were proposed with the aim of controlling the boundary layer flow and improving numerical simulations. Here, we review the different classes of turbulence coherent structures and the presumable generation mechanisms for each. The conceptual models describing the generation of turbulence coherent structures are generally classified under two categories, namely, the bottom-up mechanisms and the top-down mechanisms. The first assumes turbulence to be generated near the surface by some sort of instabilities, whereas the second assigns an active role to the large outer layer structures, perhaps the turbulent bulges. Both categories of models coexist in the flow with the first dominating turbulence generation at low Reynolds number and the second at high Reynolds number, such as the case in the atmospheric boundary layer.",book:{id:"7214",slug:"turbulence-and-related-phenomena",title:"Turbulence and Related Phenomena",fullTitle:"Turbulence and Related Phenomena"},signatures:"Zambri Harun and Eslam Reda Lotfy",authors:[{id:"243152",title:"Dr.",name:"Zambri",middleName:null,surname:"Harun",slug:"zambri-harun",fullName:"Zambri Harun"},{id:"252195",title:"Dr.",name:"Eslam",middleName:null,surname:"Reda",slug:"eslam-reda",fullName:"Eslam Reda"}]},{id:"64562",title:"Electrical Resistivity Tomography: A Subsurface-Imaging Technique",slug:"electrical-resistivity-tomography-a-subsurface-imaging-technique",totalDownloads:3182,totalCrossrefCites:7,totalDimensionsCites:10,abstract:"Electrical resistivity tomography (ERT) is a popular geophysical subsurface-imaging technique and widely applied to mineral prospecting, hydrological exploration, environmental investigation and civil engineering, as well as archaeological mapping. This chapter offers an overall review of technical aspects of ERT, which includes the fundamental theory of direct-current (DC) resistivity exploration, electrode arrays for data acquisition, numerical modelling methods and tomographic inversion algorithms. The section of fundamental theory shows basic formulae and principle of DC resistivity exploration. The section of electrode arrays summarises the previous study on all traditional-electrode arrays and recommends 4 electrode arrays for data acquisition of surface ERT and 3 electrode arrays for cross-hole ERT. The section of numerical modelling demonstrates an advanced version of finite-element method, called Gaussian quadrature grid approach, which is advantageous to a numerical simulation of ERT for complex geological models. The section of tomographic inversion presents the generalised standard conjugate gradient algorithms for both the l1- and l2-normed inversions. After that, some synthetic and real imaging examples are given to show the near-surface imaging capabilities of ERT.",book:{id:"8361",slug:"applied-geophysics-with-case-studies-on-environmental-exploration-and-engineering-geophysics",title:"Applied Geophysics with Case Studies on Environmental, Exploration and Engineering Geophysics",fullTitle:"Applied Geophysics with Case Studies on Environmental, Exploration and Engineering Geophysics"},signatures:"Bing Zhou",authors:null},{id:"17670",title:"The Qatar–South Fars Arch Development (Arabian Platform, Persian Gulf): Insights from Seismic Interpretation and Analogue Modelling",slug:"the-qatar-south-fars-arch-development-arabian-platform-persian-gulf-insights-from-seismic-interpreta",totalDownloads:8964,totalCrossrefCites:16,totalDimensionsCites:40,abstract:null,book:{id:"1297",slug:"new-frontiers-in-tectonic-research-at-the-midst-of-plate-convergence",title:"New Frontiers in Tectonic Research",fullTitle:"New Frontiers in Tectonic Research - At the Midst of Plate Convergence"},signatures:"C.R. Perotti, S. Carruba, M. Rinaldi, G. Bertozzi, L. Feltre and M. Rahimi",authors:[{id:"38310",title:"Dr.",name:"Stefano",middleName:null,surname:"Carruba",slug:"stefano-carruba",fullName:"Stefano Carruba"},{id:"42459",title:"Prof.",name:"Cesare",middleName:null,surname:"Perotti",slug:"cesare-perotti",fullName:"Cesare Perotti"},{id:"42460",title:"Dr.",name:"Marco",middleName:null,surname:"Rinaldi",slug:"marco-rinaldi",fullName:"Marco Rinaldi"},{id:"42465",title:"Dr.",name:"Giuseppe",middleName:null,surname:"Bertozzi",slug:"giuseppe-bertozzi",fullName:"Giuseppe Bertozzi"},{id:"42466",title:"Dr.",name:"Luca",middleName:null,surname:"Feltre",slug:"luca-feltre",fullName:"Luca Feltre"},{id:"42467",title:"Dr.",name:"Mashallah",middleName:null,surname:"Rahimi",slug:"mashallah-rahimi",fullName:"Mashallah Rahimi"}]}],onlineFirstChaptersFilter:{topicId:"104",limit:6,offset:0},onlineFirstChaptersCollection:[{id:"82515",title:"A Review on Elemental and Isotopic Geochemistry",slug:"a-review-on-elemental-and-isotopic-geochemistry",totalDownloads:3,totalDimensionsCites:0,doi:"10.5772/intechopen.105496",abstract:"Geochemistry is the study of the development, and distribution of chemical elements on Earth, which are found in rock-forming minerals and their byproducts, as well as in living beings, water, and the environment. The elemental geochemical variation of sediments is used to recognize the mechanisms controlling the estuarine environment and serves as a baseline for assessing the environmental effect in the future. Geochemistry is a unique field that deals with the study of mineral deposits. It also addresses the interconnections between the structures of rock, soil, water, and air, which vary according to different places. Furthermore, groundwater is the solely accessible water supply in many desert basins, particularly in developing nations. Geochemical indicators are proper instruments for addressing a diversity of hydrological issues, particularly in arid and semi-arid settings. Thermodynamically, the fugacity of oxygen (fO2) in solid earth varies by many orders of magnitude. Enstatite chondrites can have high levels of hydrogen abundance, hydrogen, and nitrogen isotope compositions like those of the earth’s mantle. The chapter deals with the basic concept of geochemistry and its types, as well as the development of geochemistry. It also explains elemental and isotopes geochemistry, human health, and medical geochemistry.",book:{id:"11139",title:"Geochemistry and Mineral Resources",coverURL:"https://cdn.intechopen.com/books/images_new/11139.jpg"},signatures:"Riyam N. Khalef, Amal I. Hassan and Hosam M. Saleh"},{id:"81757",title:"Petroleum Geochemistry",slug:"petroleum-geochemistry",totalDownloads:18,totalDimensionsCites:0,doi:"10.5772/intechopen.104709",abstract:"Petroleum geochemistry has entered its second period of growth. The first period, largely associated with conventional oil and gas, occurred in the 70s and 80s when the classic works on source rock characterization, biomarkers, depositional systems, and petroleum generation, including kinetics and basin modeling were the focus. The second period began slightly after the turn of the century as a consequence of the “unconventional resource” revolution and the interest in distressed resources developed, the focus turned to non-hydrocarbon contaminants, new interest in hydrocarbon expulsion and retention, identification of tight rock pay zones, and the development of organic porosity. This chapter will discuss source rock characterization and formation, petroleum generation, expulsion, and retention, correlation among hydrocarbon accumulations and to their source rock(s), and organic porosity.",book:{id:"11139",title:"Geochemistry and Mineral Resources",coverURL:"https://cdn.intechopen.com/books/images_new/11139.jpg"},signatures:"Mei Mei and Barry Katz"},{id:"81773",title:"Proterozoic Newer Dolerite Dyke Swarm Magmatism in the Singhbhum Craton, Eastern India",slug:"proterozoic-newer-dolerite-dyke-swarm-magmatism-in-the-singhbhum-craton-eastern-india",totalDownloads:20,totalDimensionsCites:0,doi:"10.5772/intechopen.104833",abstract:"Precambrian mafic magmatism and its role in the evolution of Earth’s crust has been paid serious attention by researchers for the last four decades. The emplacement of mafic dyke swarms acts as an important time marker in geological terrains. Number of shield terrains throughout the world has been intruded by the Precambrian dyke swarms, hence the presence of these dykes are useful to understand the Proterozoic tectonics, magmatism, crustal growth and continental reconstruction. Likewise, the Protocontinents of Indian Shield e.g. Aravalli-Bundelkhand, Dharwar, Bastar, and Singhbhum Protocontinent had experienced the dyke swarm intrusions having different characteristics and orientations. In Singhbhum craton, an impressive set of mafic dyke swarm, called as Newer dolerite dyke swarm, had intruded the Precambrian Singhbhum granitoid complex through a wide geological period from 2800 to 1100 Ma. Present chapter focuses on the published results or conclusions of these dykes in terms of their mantle source characteristics, metasomatism of the mantle source, degree of crustal contamination and partial melting processes. Geochemical characteristics of these dykes particularly Ti/Y, Zr/Y, Th/Nb, Ba/Nb, La/Nb, (La/Sm)PM are similar to either MORB or subduction zone basalts that occur along the plate margin. The enriched LREE-LILE and depletion of HFSE especially Nb, P and Ti probably indicate generation of these dykes in a subduction zone setting.",book:{id:"11139",title:"Geochemistry and Mineral Resources",coverURL:"https://cdn.intechopen.com/books/images_new/11139.jpg"},signatures:"Akhtar R. Mir"},{id:"81610",title:"Prospectivity Mapping Using Stream Sediment Geochemistry Along the Orange River Catchment for Base Metal, Prieska, Northern Cape, South Africa",slug:"prospectivity-mapping-using-stream-sediment-geochemistry-along-the-orange-river-catchment-for-base-m",totalDownloads:41,totalDimensionsCites:0,doi:"10.5772/intechopen.101785",abstract:"The Areachap Terrane, which is part of the Namaqua Sector of the Namaqua-Natal Belt in the Northern Cape Province, host volcanic-hosted Zn-Cu deposits at volcanic centres. The primary objective was to map Volcanogenic Massive Sulphide (VMS) mineralisation, determine the heavy metal contents of sediments, locate the source of anomalies and delineate targets for follow-up studies. Nine thousand three hundred and fourteen stream sediments samples collected were analysed using XRF. The element associated with their respective lithostratigraphy was calculated using spatial joint analysis tool. ArcGIS was used to display uni-elements maps and relevant multi-element maps. The delineated potential VMS mineralisation target is considered for further follow-up study. The M23 and M24 anomalies are delineated for Cu_Ni mineralisation. M23 and M24 anomalies are sourced from ultramafic debris transported from the Ghaap Group; however, this potential target will require follow-up studies for verification. The correlation between the Cu-Pb-Zn anomaly with alkali elements (Nb, Zr, Th, and U) and REEs (in Table 9) suggests there is a possibility that the M26–M29 anomaly is alkali-granitic genetic origin. The As, Ba, Ce, Cr, Cu, Hf, Nd, Ni, Rb, Sr., S, V, Zr and Zn contents showed a heterogeneous spatial distribution, reflected by high coefficient of variation and large standard deviation.",book:{id:"11139",title:"Geochemistry and Mineral Resources",coverURL:"https://cdn.intechopen.com/books/images_new/11139.jpg"},signatures:"Nthabiseng Mashale"},{id:"81376",title:"Geochemistry Applied to the Exploration of Mineral Deposits",slug:"geochemistry-applied-to-the-exploration-of-mineral-deposits",totalDownloads:26,totalDimensionsCites:0,doi:"10.5772/intechopen.103941",abstract:"Geochemistry can be applied to the exploration of mineral deposits, for which it is necessary to understand the fundamentals of geochemical prospecting, the geochemical dispersion of elements based on their chemical properties. This chapter presents the basics of geochemical prospecting including: element mobility depending on ionic potential, pH, and Eh, with examples of Cu mobility during supergenic alteration of a primary sulfide deposit, a brief overview of sampling/geochemical prospecting methods, as well as a case study of the geochemical prospecting study carried out in the vanadium (V), uranium (U), and zinc (Zn) sedimentary mineral deposit of Puyango, Ecuador, in which anomalous and subanomalous values were detected in rock samples of various pathfinder elements of V and U.",book:{id:"11139",title:"Geochemistry and Mineral Resources",coverURL:"https://cdn.intechopen.com/books/images_new/11139.jpg"},signatures:"John Luis Manrique Carreño"}],onlineFirstChaptersTotal:5},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:0,limit:8,total:null},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:90,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:104,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:32,numberOfPublishedChapters:320,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:13,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:11,numberOfPublishedChapters:141,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:8,numberOfPublishedChapters:133,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:114,numberOfOpenTopics:3,numberOfUpcomingTopics:1,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:107,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:19,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:7,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:0,numberOfPublishedChapters:17,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:null,doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. The whole process of submitting an article and editing of the submitted article goes extremely smooth and fast, the number of reads and downloads of chapters is high, and the contributions are also frequently cited.",author:{id:"55578",name:"Antonio",surname:"Jurado-Navas",institutionString:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",slug:"antonio-jurado-navas",institution:{id:"720",name:"University of Malaga",country:{id:null,name:"Spain"}}}},{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}}]},series:{item:{id:"24",title:"Sustainable Development",doi:"10.5772/intechopen.100361",issn:null,scope:"
\r\n\tTransforming our World: the 2030 Agenda for Sustainable Development endorsed by United Nations and 193 Member States, came into effect on Jan 1, 2016, to guide decision making and actions to the year 2030 and beyond. Central to this Agenda are 17 Goals, 169 associated targets and over 230 indicators that are reviewed annually. The vision envisaged in the implementation of the SDGs is centered on the five Ps: People, Planet, Prosperity, Peace and Partnership. This call for renewed focused efforts ensure we have a safe and healthy planet for current and future generations.
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\r\n\tThis Series focuses on covering research and applied research involving the five Ps through the following topics:
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\r\n\t1. Sustainable Economy and Fair Society that relates to SDG 1 on No Poverty, SDG 2 on Zero Hunger, SDG 8 on Decent Work and Economic Growth, SDG 10 on Reduced Inequalities, SDG 12 on Responsible Consumption and Production, and SDG 17 Partnership for the Goals
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\r\n\t2. Health and Wellbeing focusing on SDG 3 on Good Health and Wellbeing and SDG 6 on Clean Water and Sanitation
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\r\n\t3. Inclusivity and Social Equality involving SDG 4 on Quality Education, SDG 5 on Gender Equality, and SDG 16 on Peace, Justice and Strong Institutions
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\r\n\t4. Climate Change and Environmental Sustainability comprising SDG 13 on Climate Action, SDG 14 on Life Below Water, and SDG 15 on Life on Land
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\r\n\t5. Urban Planning and Environmental Management embracing SDG 7 on Affordable Clean Energy, SDG 9 on Industry, Innovation and Infrastructure, and SDG 11 on Sustainable Cities and Communities.
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\r\n\tThe series also seeks to support the use of cross cutting SDGs, as many of the goals listed above, targets and indicators are all interconnected to impact our lives and the decisions we make on a daily basis, making them impossible to tie to a single topic.
",coverUrl:"https://cdn.intechopen.com/series/covers/24.jpg",latestPublicationDate:"July 6th, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:0,editor:{id:"262440",title:"Prof.",name:"Usha",middleName:null,surname:"Iyer-Raniga",slug:"usha-iyer-raniga",fullName:"Usha Iyer-Raniga",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRYSXQA4/Profile_Picture_2022-02-28T13:55:36.jpeg",biography:"Usha Iyer-Raniga is a professor in the School of Property and Construction Management at RMIT University. Usha co-leads the One Planet Network’s Sustainable Buildings and Construction Programme (SBC), a United Nations 10 Year Framework of Programmes on Sustainable Consumption and Production (UN 10FYP SCP) aligned with Sustainable Development Goal 12. The work also directly impacts SDG 11 on Sustainable Cities and Communities. She completed her undergraduate degree as an architect before obtaining her Masters degree from Canada and her Doctorate in Australia. Usha has been a keynote speaker as well as an invited speaker at national and international conferences, seminars and workshops. Her teaching experience includes teaching in Asian countries. She has advised Austrade, APEC, national, state and local governments. She serves as a reviewer and a member of the scientific committee for national and international refereed journals and refereed conferences. She is on the editorial board for refereed journals and has worked on Special Issues. Usha has served and continues to serve on the Boards of several not-for-profit organisations and she has also served as panel judge for a number of awards including the Premiers Sustainability Award in Victoria and the International Green Gown Awards. Usha has published over 100 publications, including research and consulting reports. Her publications cover a wide range of scientific and technical research publications that include edited books, book chapters, refereed journals, refereed conference papers and reports for local, state and federal government clients. She has also produced podcasts for various organisations and participated in media interviews. She has received state, national and international funding worth over USD $25 million. Usha has been awarded the Quarterly Franklin Membership by London Journals Press (UK). Her biography has been included in the Marquis Who's Who in the World® 2018, 2016 (33rd Edition), along with approximately 55,000 of the most accomplished men and women from around the world, including luminaries as U.N. Secretary-General Ban Ki-moon. In 2017, Usha was awarded the Marquis Who’s Who Lifetime Achiever Award.",institutionString:null,institution:{name:"RMIT University",institutionURL:null,country:{name:"Australia"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:5,paginationItems:[{id:"91",title:"Sustainable Economy and Fair Society",coverUrl:"https://cdn.intechopen.com/series_topics/covers/91.jpg",isOpenForSubmission:!0,editor:{id:"181603",title:"Dr.",name:"Antonella",middleName:null,surname:"Petrillo",slug:"antonella-petrillo",fullName:"Antonella Petrillo",profilePictureURL:"https://mts.intechopen.com/storage/users/181603/images/system/181603.jpg",biography:"Antonella Petrillo is a Professor at the Department of Engineering of the University of Naples “Parthenope”, Italy. She received her Ph.D. in Mechanical Engineering from the University of Cassino. Her research interests include multi-criteria decision analysis, industrial plant, logistics, manufacturing and safety. She serves as an Associate Editor for the International Journal of the Analytic Hierarchy Process. She is a member of AHP Academy and a member of several editorial boards. She has over 160 Scientific Publications in International Journals and Conferences and she is the author of 5 books on Innovation and Decision Making in Industrial Applications and Engineering.",institutionString:null,institution:{name:"Parthenope University of Naples",institutionURL:null,country:{name:"Italy"}}},editorTwo:null,editorThree:null},{id:"92",title:"Health and Wellbeing",coverUrl:"https://cdn.intechopen.com/series_topics/covers/92.jpg",isOpenForSubmission:!0,editor:{id:"348225",title:"Prof.",name:"Ann",middleName:null,surname:"Hemingway",slug:"ann-hemingway",fullName:"Ann Hemingway",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000035LZFoQAO/Profile_Picture_2022-04-11T14:55:40.jpg",biography:"Professor Hemingway is a public health researcher, Bournemouth University, undertaking international and UK research focused on reducing inequalities in health outcomes for marginalised and excluded populations and more recently focused on equine assisted interventions.",institutionString:null,institution:{name:"Bournemouth University",institutionURL:null,country:{name:"United Kingdom"}}},editorTwo:null,editorThree:null},{id:"93",title:"Inclusivity and Social Equity",coverUrl:"https://cdn.intechopen.com/series_topics/covers/93.jpg",isOpenForSubmission:!0,editor:{id:"210060",title:"Prof. Dr.",name:"Ebba",middleName:null,surname:"Ossiannilsson",slug:"ebba-ossiannilsson",fullName:"Ebba Ossiannilsson",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002g6LkBQAU/Profile_Picture_2022-02-28T13:31:48.png",biography:"Professor Dr. Ebba Ossiannilsson is an independent researcher, expert, consultant, quality auditor and influencer in the fields of open, flexible online and distance learning (OFDL) and the 'new normal'. Her focus is on quality, innovation, leadership, and personalised learning. She works primarily at the strategic and policy levels, both nationally and internationally, and with key international organisations. She is committed to promoting and improving OFDL in the context of SDG4 and the future of education. Ossiannilsson has more than 20 years of experience in her current field, but more than 40 years in the education sector. She works as a reviewer and expert for the European Commission and collaborates with the Joint Research Centre for Quality in Open Education. Ossiannilsson also collaborates with ITCILO and ICoBC (International Council on Badges and Credentials). She is a member of the ICDE Board of Directors and has previously served on the boards of EDEN and EUCEN. Ossiannilsson is a quality expert and reviewer for ICDE, EDEN and the EADTU. She chairs the ICDE OER Advocacy Committee and is a member of the ICDE Quality Network. She is regularly invited as a keynote speaker at conferences. She is a guest editor for several special issues and a member of the editorial board of several scientific journals. She has published more than 200 articles and is currently working on book projects in the field of OFDL. Ossiannilsson is a visiting professor at several international universities and was recently appointed Professor and Research Fellow at Victoria University of Wellington, NZ. Ossiannilsson has been awarded the following fellowships: EDEN Fellows, EDEN Council of Fellows, and Open Education Europe. She is a ICDE OER Ambassador, Open Education Europe Ambassador, GIZ Ambassador for Quality in Digital Learning, and part of the Globe-Community of Digital Learning and Champion of SPARC Europe. On a national level, she is a quality developer at the Swedish Institute for Standards (SIS) and for ISO. She is a member of the Digital Skills and Jobs Coalition Sweden and Vice President of the Swedish Association for Distance Education. She is currently working on a government initiative on quality in distance education at the National Council for Higher Education. 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He is on the editorial board of several international peer-reviewed journals and has published many papers. Additionally, he has participated in many international and national congresses, seminars, and workshops with oral and poster presentations. He is an active member of many local and international organizations.",institutionString:"İskenderun Technical University",institution:{name:"İskenderun Technical University",country:{name:"Turkey"}}},{id:"61139",title:"Dr.",name:"Sergey",middleName:null,surname:"Tkachev",slug:"sergey-tkachev",fullName:"Sergey Tkachev",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/61139/images/system/61139.png",biography:"Dr. Sergey Tkachev is a senior research scientist at the Institute of Fundamental Medicine and Biology, Kazan Federal University, Russia, and at the Institute of Chemical Biology and Fundamental Medicine SB RAS, Novosibirsk, Russia. He received his Ph.D. in Molecular Biology with his thesis “Genetic variability of the tick-borne encephalitis virus in natural foci of Novosibirsk city and its suburbs.” His primary field is molecular virology with research emphasis on vector-borne viruses, especially tick-borne encephalitis virus, Kemerovo virus and Omsk hemorrhagic fever virus, rabies virus, molecular genetics, biology, and epidemiology of virus pathogens.",institutionString:"Russian Academy of Sciences",institution:{name:"Russian Academy of Sciences",country:{name:"Russia"}}},{id:"310962",title:"Dr.",name:"Amlan",middleName:"Kumar",surname:"Patra",slug:"amlan-patra",fullName:"Amlan Patra",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/310962/images/system/310962.jpg",biography:"Amlan K. Patra, FRSB, obtained a Ph.D. in Animal Nutrition from Indian Veterinary Research Institute, India, in 2002. He is currently an associate professor at West Bengal University of Animal and Fishery Sciences. He has more than twenty years of research and teaching experience. He held previous positions at the American Institute for Goat Research, The Ohio State University, Columbus, USA, and Free University of Berlin, Germany. His research focuses on animal nutrition, particularly ruminants and poultry nutrition, gastrointestinal electrophysiology, meta-analysis and modeling in nutrition, and livestock–environment interaction. He has authored around 175 articles in journals, book chapters, and proceedings. Dr. Patra serves on the editorial boards of several reputed journals.",institutionString:null,institution:{name:"West Bengal University of Animal and Fishery Sciences",country:{name:"India"}}},{id:"53998",title:"Prof.",name:"László",middleName:null,surname:"Babinszky",slug:"laszlo-babinszky",fullName:"László Babinszky",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/53998/images/system/53998.png",biography:"László Babinszky is Professor Emeritus, Department of Animal Nutrition Physiology, University of Debrecen, Hungary. He has also worked in the Department of Animal Nutrition, University of Wageningen, Netherlands; the Institute for Livestock Feeding and Nutrition (IVVO), Lelystad, Netherlands; the Agricultural University of Vienna (BOKU); the Institute for Animal Breeding and Nutrition, Austria; and the Oscar Kellner Research Institute for Animal Nutrition, Rostock, Germany. In 1992, Dr. Babinszky obtained a Ph.D. in Animal Nutrition from the University of Wageningen. His main research areas are swine and poultry nutrition. He has authored more than 300 publications (papers, book chapters) and edited four books and fourteen international conference proceedings.",institutionString:"University of Debrecen",institution:{name:"University of Debrecen",country:{name:"Hungary"}}},{id:"201830",title:"Dr.",name:"Fernando",middleName:"Sanchez",surname:"Davila",slug:"fernando-davila",fullName:"Fernando Davila",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/201830/images/5017_n.jpg",biography:"I am a professor at UANL since 1988. My research lines are the development of reproductive techniques in small ruminants. We also conducted research on sexual and social behavior in males.\nI am Mexican and study my professional career as an engineer in agriculture and animal science at UANL. Then take a masters degree in science in Germany (Animal breeding). Take a doctorate in animal science at the UANL.",institutionString:null,institution:{name:"Universidad Autónoma de Nuevo León",country:{name:"Mexico"}}},{id:"309250",title:"Dr.",name:"Miguel",middleName:null,surname:"Quaresma",slug:"miguel-quaresma",fullName:"Miguel Quaresma",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/309250/images/9059_n.jpg",biography:"Miguel Nuno Pinheiro Quaresma was born on May 26, 1974 in Dili, Timor Island. He is married with two children: a boy and a girl, and he is a resident in Vila Real, Portugal. He graduated in Veterinary Medicine in August 1998 and obtained his Ph.D. degree in Veterinary Sciences -Clinical Area in February 2015, both from the University of Trás-os-Montes e Alto Douro. He is currently enrolled in the Alternative Residency of the European College of Animal Reproduction. He works as a Senior Clinician at the Veterinary Teaching Hospital of UTAD (HVUTAD) with a role in clinical activity in the area of livestock and equine species as well as to support teaching and research in related areas. He teaches as an Invited Professor in Reproduction Medicine I and II of the Master\\'s in Veterinary Medicine degree at UTAD. Currently, he holds the position of Chairman of the Portuguese Buiatrics Association. He is a member of the Consultive Group on Production Animals of the OMV. He has 19 publications in indexed international journals (ISIS), as well as over 60 publications and oral presentations in both Portuguese and international journals and congresses.",institutionString:"University of Trás-os-Montes and Alto Douro",institution:{name:"University of Trás-os-Montes and Alto Douro",country:{name:"Portugal"}}},{id:"38652",title:"Prof.",name:"Rita",middleName:null,surname:"Payan-Carreira",slug:"rita-payan-carreira",fullName:"Rita Payan-Carreira",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRiFPQA0/Profile_Picture_1614601496313",biography:"Rita Payan Carreira earned her Veterinary Degree from the Faculty of Veterinary Medicine in Lisbon, Portugal, in 1985. She obtained her Ph.D. in Veterinary Sciences from the University of Trás-os-Montes e Alto Douro, Portugal. After almost 32 years of teaching at the University of Trás-os-Montes and Alto Douro, she recently moved to the University of Évora, Department of Veterinary Medicine, where she teaches in the field of Animal Reproduction and Clinics. Her primary research areas include the molecular markers of the endometrial cycle and the embryo–maternal interaction, including oxidative stress and the reproductive physiology and disorders of sexual development, besides the molecular determinants of male and female fertility. She often supervises students preparing their master's or doctoral theses. She is also a frequent referee for various journals.",institutionString:null,institution:{name:"University of Évora",country:{name:"Portugal"}}},{id:"283019",title:"Dr.",name:"Oudessa",middleName:null,surname:"Kerro Dego",slug:"oudessa-kerro-dego",fullName:"Oudessa Kerro Dego",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/283019/images/system/283019.png",biography:"Dr. Kerro Dego is a veterinary microbiologist with training in veterinary medicine, microbiology, and anatomic pathology. Dr. Kerro Dego is an assistant professor of dairy health in the department of animal science, the University of Tennessee, Institute of Agriculture, Knoxville, Tennessee. He received his D.V.M. (1997), M.S. (2002), and Ph.D. (2008) degrees in Veterinary Medicine, Animal Pathology and Veterinary Microbiology from College of Veterinary Medicine, Addis Ababa University, Ethiopia; College of Veterinary Medicine, Utrecht University, the Netherlands and Western College of Veterinary Medicine, University of Saskatchewan, Canada respectively. He did his Postdoctoral training in microbial pathogenesis (2009 - 2015) in the Department of Animal Science, the University of Tennessee, Institute of Agriculture, Knoxville, Tennessee. Dr. Kerro Dego’s research focuses on the prevention and control of infectious diseases of farm animals, particularly mastitis, improving dairy food safety, and mitigation of antimicrobial resistance. Dr. Kerro Dego has extensive experience in studying the pathogenesis of bacterial infections, identification of virulence factors, and vaccine development and efficacy testing against major bacterial mastitis pathogens. Dr. Kerro Dego conducted numerous controlled experimental and field vaccine efficacy studies, vaccination, and evaluation of immunological responses in several species of animals, including rodents (mice) and large animals (bovine and ovine).",institutionString:"University of Tennessee at Knoxville",institution:{name:"University of Tennessee at Knoxville",country:{name:"United States of America"}}},{id:"251314",title:"Dr.",name:"Juan Carlos",middleName:null,surname:"Gardón",slug:"juan-carlos-gardon",fullName:"Juan Carlos Gardón",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/251314/images/system/251314.jpeg",biography:"Juan Carlos Gardón Poggi received University degree from the Faculty of Agrarian Science in Argentina, in 1983. Also he received Masters Degree and PhD from Córdoba University, Spain. He is currently a Professor at the Catholic University of Valencia San Vicente Mártir, at the Department of Medicine and Animal Surgery. He teaches diverse courses in the field of Animal Reproduction and he is the Director of the Veterinary Farm. He also participates in academic postgraduate activities at the Veterinary Faculty of Murcia University, Spain. His research areas include animal physiology, physiology and biotechnology of reproduction either in males or females, the study of gametes under in vitro conditions and the use of ultrasound as a complement to physiological studies and development of applied biotechnologies. Routinely, he supervises students preparing their doctoral, master thesis or final degree projects.",institutionString:"Catholic University of Valencia San Vicente Mártir, Spain",institution:{name:"Valencia Catholic University Saint Vincent Martyr",country:{name:"Spain"}}},{id:"125292",title:"Dr.",name:"Katy",middleName:null,surname:"Satué Ambrojo",slug:"katy-satue-ambrojo",fullName:"Katy Satué Ambrojo",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/125292/images/system/125292.jpeg",biography:"Katy Satué Ambrojo received her Veterinary Medicine degree, Master degree in Equine Technology and doctorate in Veterinary Medicine from the Faculty of Veterinary, CEU-Cardenal Herrera University in Valencia, Spain. She is a Full Professor at the Department of Medicine and Animal Surgery at the same University. She developed her research activity in the field of Endocrinology, Hematology, Biochemistry and Immunology of horses. She is a scientific reviewer of several international journals : American Journal of Obstetrics and Gynecology, Comparative Clinical Pathology, Veterinary Clinical Pathology, Journal of Equine Veterinary Science, Reproduction in Domestic Animals, Research Veterinary Science, Brazilian Journal of Medical and Biological Research, Livestock Production Science and Theriogenology. Since 2014, she has been the Head of the Clinical Analysis Laboratory of the Hospital Clínico Veterinario from the Faculty of Veterinary, CEU-Cardenal Herrera University.",institutionString:"CEU-Cardenal Herrera University",institution:{name:"CEU Cardinal Herrera University",country:{name:"Spain"}}},{id:"309529",title:"Dr.",name:"Albert",middleName:null,surname:"Rizvanov",slug:"albert-rizvanov",fullName:"Albert Rizvanov",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/309529/images/9189_n.jpg",biography:'Albert A. Rizvanov is a Professor and Director of the Center for Precision and Regenerative Medicine at the Institute of Fundamental Medicine and Biology, Kazan Federal University (KFU), Russia. He is the Head of the Center of Excellence “Regenerative Medicine” and Vice-Director of Strategic Academic Unit \\"Translational 7P Medicine\\". Albert completed his Ph.D. at the University of Nevada, Reno, USA and Dr.Sci. at KFU. He is a corresponding member of the Tatarstan Academy of Sciences, Russian Federation. Albert is an author of more than 300 peer-reviewed journal articles and 22 patents. He has supervised 11 Ph.D. and 2 Dr.Sci. dissertations. Albert is the Head of the Dissertation Committee on Biochemistry, Microbiology, and Genetics at KFU.\nORCID https://orcid.org/0000-0002-9427-5739\nWebsite https://kpfu.ru/Albert.Rizvanov?p_lang=2',institutionString:"Kazan Federal University",institution:{name:"Kazan Federal University",country:{name:"Russia"}}},{id:"210551",title:"Dr.",name:"Arbab",middleName:null,surname:"Sikandar",slug:"arbab-sikandar",fullName:"Arbab Sikandar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/210551/images/system/210551.jpg",biography:"Dr. Arbab Sikandar, PhD, M. Phil, DVM was born on April 05, 1981. He is currently working at the College of Veterinary & Animal Sciences as an Assistant Professor. He previously worked as a lecturer at the same University. \nHe is a Member/Secretory of Ethics committee (No. CVAS-9377 dated 18-04-18), Member of the QEC committee CVAS, Jhang (Regr/Gen/69/873, dated 26-10-2017), Member, Board of studies of Department of Basic Sciences (No. CVAS. 2851 Dated. 12-04-13, and No. CVAS, 9024 dated 20/11/17), Member of Academic Committee, CVAS, Jhang (No. CVAS/2004, Dated, 25-08-12), Member of the technical committee (No. CVAS/ 4085, dated 20,03, 2010 till 2016).\n\nDr. Arbab Sikandar contributed in five days hands-on-training on Histopathology at the Department of Pathology, UVAS from 12-16 June 2017. He received a Certificate of appreciation for contributions for Popularization of Science and Technology in the Society on 17-11-15. He was the resource person in the lecture series- ‘scientific writing’ at the Department of Anatomy and Histology, UVAS, Lahore on 29th October 2015. He won a full fellowship as a principal candidate for the year 2015 in the field of Agriculture, EICA, Egypt with ref. to the Notification No. 12(11) ACS/Egypt/2014 from 10 July 2015 to 25th September 2015.; he received a grant of Rs. 55000/- as research incentives from Director, Advanced Studies and Research, UVAS, Lahore upon publications of research papers in IF Journals (DR/215, dated 19-5-2014.. He obtained his PhD by winning a HEC Pakistan indigenous Scholarship, ‘Ph.D. fellowship for 5000 scholars – Phase II’ (2av1-147), 17-6/HEC/HRD/IS-II/12, November 15, 2012. \n\nDr. Sikandar is a member of numerous societies: Registered Veterinary Medical Practitioner (life member) and Registered Veterinary Medical Faculty of Pakistan Veterinary Medical Council. The Registration code of PVMC is RVMP/4298 and RVMF/ 0102.; Life member of the University of Veterinary and Animal Sciences, Lahore, Alumni Association with S# 664, dated: 6-4-12. ; Member 'Vets Care Organization Pakistan” with Reference No. VCO-605-149, dated 05-04-06. :Member 'Vet Crescent” (Society of Animal Health and Production), UVAS, Lahore.",institutionString:"University of Veterinary & Animal Science",institution:{name:"University of Veterinary and Animal Sciences",country:{name:"Pakistan"}}},{id:"311663",title:"Dr.",name:"Prasanna",middleName:null,surname:"Pal",slug:"prasanna-pal",fullName:"Prasanna Pal",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/311663/images/13261_n.jpg",biography:null,institutionString:null,institution:{name:"National Dairy Research Institute",country:{name:"India"}}},{id:"202192",title:"Dr.",name:"Catrin",middleName:null,surname:"Rutland",slug:"catrin-rutland",fullName:"Catrin Rutland",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/202192/images/system/202192.png",biography:"Catrin Rutland is an Associate Professor of Anatomy and Developmental Genetics at the University of Nottingham, UK. She obtained a BSc from the University of Derby, England, a master’s degree from Technische Universität München, Germany, and a Ph.D. from the University of Nottingham. She undertook a post-doctoral research fellowship in the School of Medicine before accepting tenure in Veterinary Medicine and Science. Dr. Rutland also obtained an MMedSci (Medical Education) and a Postgraduate Certificate in Higher Education (PGCHE). She is the author of more than sixty peer-reviewed journal articles, twelve books/book chapters, and more than 100 research abstracts in cardiovascular biology and oncology. She is a board member of the European Association of Veterinary Anatomists, Fellow of the Anatomical Society, and Senior Fellow of the Higher Education Academy. Dr. Rutland has also written popular science books for the public. https://orcid.org/0000-0002-2009-4898. www.nottingham.ac.uk/vet/people/catrin.rutland",institutionString:null,institution:{name:"University of Nottingham",country:{name:"United Kingdom"}}},{id:"283315",title:"Prof.",name:"Samir",middleName:null,surname:"El-Gendy",slug:"samir-el-gendy",fullName:"Samir El-Gendy",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRduYQAS/Profile_Picture_1606215849748",biography:"Samir El-Gendy is a Professor of anatomy and embryology at the faculty of veterinary medicine, Alexandria University, Egypt. Samir obtained his PhD in veterinary science in 2007 from the faculty of veterinary medicine, Alexandria University and has been a professor since 2017. Samir is an author on 24 articles at Scopus and 12 articles within local journals and 2 books/book chapters. His research focuses on applied anatomy, imaging techniques and computed tomography. Samir worked as a member of different local projects on E-learning and he is a board member of the African Association of Veterinary Anatomists and of anatomy societies and as an associated author at local and international journals. Orcid: https://orcid.org/0000-0002-6180-389X",institutionString:null,institution:{name:"Alexandria University",country:{name:"Egypt"}}},{id:"246149",title:"Dr.",name:"Valentina",middleName:null,surname:"Kubale",slug:"valentina-kubale",fullName:"Valentina Kubale",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/246149/images/system/246149.jpg",biography:"Valentina Kubale is Associate Professor of Veterinary Medicine at the Veterinary Faculty, University of Ljubljana, Slovenia. Since graduating from the Veterinary faculty she obtained her PhD in 2007, performed collaboration with the Department of Pharmacology, University of Copenhagen, Denmark. She continued as a post-doctoral fellow at the University of Copenhagen with a Lundbeck foundation fellowship. She is the editor of three books and author/coauthor of 23 articles in peer-reviewed scientific journals, 16 book chapters, and 68 communications at scientific congresses. Since 2008 she has been the Editor Assistant for the Slovenian Veterinary Research journal. She is a member of Slovenian Biochemical Society, The Endocrine Society, European Association of Veterinary Anatomists and Society for Laboratory Animals, where she is board member.",institutionString:"University of Ljubljana",institution:{name:"University of Ljubljana",country:{name:"Slovenia"}}},{id:"258334",title:"Dr.",name:"Carlos Eduardo",middleName:null,surname:"Fonseca-Alves",slug:"carlos-eduardo-fonseca-alves",fullName:"Carlos Eduardo Fonseca-Alves",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/258334/images/system/258334.jpg",biography:"Dr. Fonseca-Alves earned his DVM from Federal University of Goias – UFG in 2008. He completed an internship in small animal internal medicine at UPIS university in 2011, earned his MSc in 2013 and PhD in 2015 both in Veterinary Medicine at Sao Paulo State University – UNESP. Dr. Fonseca-Alves currently serves as an Assistant Professor at Paulista University – UNIP teaching small animal internal medicine.",institutionString:null,institution:{name:"Universidade Paulista",country:{name:"Brazil"}}},{id:"245306",title:"Dr.",name:"María Luz",middleName:null,surname:"Garcia Pardo",slug:"maria-luz-garcia-pardo",fullName:"María Luz Garcia Pardo",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/245306/images/system/245306.png",biography:"María de la Luz García Pardo is an agricultural engineer from Universitat Politècnica de València, Spain. She has a Ph.D. in Animal Genetics. Currently, she is a lecturer at the Agrofood Technology Department of Miguel Hernández University, Spain. Her research is focused on genetics and reproduction in rabbits. The major goal of her research is the genetics of litter size through novel methods such as selection by the environmental sensibility of litter size, with forays into the field of animal welfare by analysing the impact on the susceptibility to diseases and stress of the does. Details of her publications can be found at https://orcid.org/0000-0001-9504-8290.",institutionString:null,institution:{name:"Miguel Hernandez University",country:{name:"Spain"}}},{id:"350704",title:"M.Sc.",name:"Camila",middleName:"Silva Costa",surname:"Ferreira",slug:"camila-ferreira",fullName:"Camila Ferreira",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/350704/images/17280_n.jpg",biography:"Graduated in Veterinary Medicine at the Fluminense Federal University, specialist in Equine Reproduction at the Brazilian Veterinary Institute (IBVET) and Master in Clinical Veterinary Medicine and Animal Reproduction at the Fluminense Federal University. She has experience in analyzing zootechnical indices in dairy cattle and organizing events related to Veterinary Medicine through extension grants. I have experience in the field of diagnostic imaging and animal reproduction in veterinary medicine through monitoring and scientific initiation scholarships. I worked at the Equus Central Reproduction Equine located in Santo Antônio de Jesus – BA in the 2016/2017 breeding season. I am currently a doctoral student with a scholarship from CAPES of the Postgraduate Program in Veterinary Medicine (Pathology and Clinical Sciences) at the Federal Rural University of Rio de Janeiro (UFRRJ) with a research project with an emphasis on equine endometritis.",institutionString:null,institution:null},{id:"41319",title:"Prof.",name:"Lung-Kwang",middleName:null,surname:"Pan",slug:"lung-kwang-pan",fullName:"Lung-Kwang Pan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/41319/images/84_n.jpg",biography:null,institutionString:null,institution:null},{id:"201721",title:"Dr.",name:"Beatrice",middleName:null,surname:"Funiciello",slug:"beatrice-funiciello",fullName:"Beatrice Funiciello",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/201721/images/11089_n.jpg",biography:"Graduated from the University of Milan in 2011, my post-graduate education included CertAVP modules mainly on equines (dermatology and internal medicine) and a few on small animal (dermatology and anaesthesia) at the University of Liverpool. After a general CertAVP (2015) I gained the designated Certificate in Veterinary Dermatology (2017) after taking the synoptic examination and then applied for the RCVS ADvanced Practitioner status. After that, I completed the Postgraduate Diploma in Veterinary Professional Studies at the University of Liverpool (2018). My main area of work is cross-species veterinary dermatology.",institutionString:null,institution:null},{id:"291226",title:"Dr.",name:"Monica",middleName:null,surname:"Cassel",slug:"monica-cassel",fullName:"Monica Cassel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/291226/images/8232_n.jpg",biography:'Degree in Biological Sciences at the Federal University of Mato Grosso with scholarship for Scientific Initiation by FAPEMAT (2008/1) and CNPq (2008/2-2009/2): Project \\"Histological evidence of reproductive activity in lizards of the Manso region, Chapada dos Guimarães, Mato Grosso, Brazil\\". Master\\\'s degree in Ecology and Biodiversity Conservation at Federal University of Mato Grosso with a scholarship by CAPES/REUNI program: Project \\"Reproductive biology of Melanorivulus punctatus\\". PhD\\\'s degree in Science (Cell and Tissue Biology Area) \n at University of Sao Paulo with scholarship granted by FAPESP; Project \\"Development of morphofunctional changes in ovary of Astyanax altiparanae Garutti & Britski, 2000 (Teleostei, Characidae)\\". She has experience in Reproduction of vertebrates and Morphology, with emphasis in Cellular Biology and Histology. She is currently a teacher in the medium / technical level courses at IFMT-Alta Floresta, as well as in the Bachelor\\\'s degree in Animal Science and in the Bachelor\\\'s degree in Business.',institutionString:null,institution:null},{id:"442807",title:"Dr.",name:"Busani",middleName:null,surname:"Moyo",slug:"busani-moyo",fullName:"Busani Moyo",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Gwanda State University",country:{name:"Zimbabwe"}}},{id:"439435",title:"Dr.",name:"Feda S.",middleName:null,surname:"Aljaser",slug:"feda-s.-aljaser",fullName:"Feda S. 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