\r\n\t• Role of technological innovation and corporate risk management \r\n\t• Challenges for corporate governance while launching corporate environmental management among emerging economies \r\n\t• Demonstrating the relationship between environmental risk management and sustainable management \r\n\t• Contemplating strategic corporate environmental responsibility under the influence of cultural barriers \r\n\t• Risk management in different countries – the international management dimension \r\n\t• Global Standardization vs local adaptation of corporate environmental risk management in multinational corporations. \r\n\t• Is there a transnational approach to environmental risk management? \r\n\t• Approaches towards Risk management strategies in the short-term and long-term.
",isbn:"978-1-83968-906-2",printIsbn:"978-1-83968-905-5",pdfIsbn:"978-1-83968-907-9",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,hash:"9b65afaff43ec930bc6ee52c4aa1f78f",bookSignature:"Dr. Muddassar Sarfraz and Prof. Larisa Ivascu",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/10226.jpg",keywords:"Global Risk Management, Risk Assessment, Climate Risk, Environmental Management, International Business, Business Sustainability, Corporate Governance, Financial Market, Financial Risks, Sustainable Economic Environment, Business Valuation, Organizational Behavior",numberOfDownloads:131,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfDimensionsCitations:0,numberOfTotalCitations:0,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"September 24th 2020",dateEndSecondStepPublish:"October 22nd 2020",dateEndThirdStepPublish:"December 21st 2020",dateEndFourthStepPublish:"March 11th 2021",dateEndFifthStepPublish:"May 10th 2021",remainingDaysToSecondStep:"4 months",secondStepPassed:!0,currentStepOfPublishingProcess:4,editedByType:null,kuFlag:!1,biosketch:"Dr. Muddassar Sarfraz focuses on corporate social responsibility, human resource management, strategic management, and business management. 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He holds an International Master of Business Administration (IMBA) from Chongqing University (China) and Master of Business Administration (HR) from The University of Lahore. He has published tens of papers in foreign authoritative journals and academic conferences both at home and abroad.\nHe is the Book Editor of Sustainable Management Practices, Analyzing the Relationship between Corporate Governance, CSR, Sustainability, and Cogitating the Interconnection between Corporate Social Responsibility and Sustainability. He is the Associate and Guest Editor of Frontiers in Psychology, International Journal of Humanities and Social Development Research and the Journal of Science and Innovative Technologies. He is an Editorial Board Member of the International Journal of Human Resource as well as a member of the British Academy of Management (UK), Chinese Economists Society (USA), World Economic Association (UK), American Economic Association (USA), and an Ambassador of the International MBA program of Chongqing University, PR China, for Pakistan. \nHis research focuses on corporate social responsibility, human resource management, strategic management, and business management.",institutionString:"Binjiang College, Nanjing University of Information Science &Technology, Wuxi, Jiangsu",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"1",institution:null}],coeditorOne:{id:"288698",title:"Prof.",name:"Larisa",middleName:null,surname:"Ivascu",slug:"larisa-ivascu",fullName:"Larisa Ivascu",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRfMOQA0/Profile_Picture_1594716735521",biography:"Dr Larisa IVAȘCU is currently an associate professor at the Politehnica University of Timisoara. 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\n
1. Introduction
\n
Safe, effective, high-quality, and affordable medicines are essential for the achievement of positive, equitable health outcomes [1]. They are necessary for the prevention and treatment of serious public health threats, and for the achievement of the global health goals [2]. However, there is growing concern regarding the increasing availability and use of poor-quality medicines, particularly in developing countries in Africa, Asia, and South America [3–7].
\n
Poor-quality medicines include those that have been falsified (i.e., deliberately and fraudulently mislabeled with respect to identity and/or source) and substandard medicines (i.e., products resulting from poor manufacturing with no intent to deceive and usually with inadequate or too much active pharmaceutical ingredient) [2].
\n
Falsified medicines have resulted in billions of dollars in illegal annual revenues going to criminals and have caused prolonged, severe illness and deaths. Falsified drugs particularly affect the most disadvantaged people in poor countries [5].
\n
In particular, the use of substandard antimalarial agents has been reported [3, 4, 7–18]. A World Health Organization (WHO) survey of antimalarial medicine quality in six countries from sub-Saharan Africa discovered that nearly 30% of the fully tested samples of medications failed to comply with internationally recognized quality specifications [8]. Similarly, a review reported that approximately one third of antimalarial medication samples from sub-Saharan Africa, as well as from Southeast Asia, failed chemical assay analysis [3].
\n
Factors contributing to poor-quality medicines are numerous [3]. In many developing countries, for example, first-line artemisinin-based combination therapy (ACT) cannot be afforded by many patients [4, 5]. Consequently, patients tend to procure cheaper alternatives that may be falsified or substandard and that may contain subtherapeutic amounts of the active pharmaceutical ingredients (APIs) or only one of the two active ingredients of the ACT [2, 12]. Thus, the use of such poor-quality antimalarial agents leads to increases in morbidity and mortality [19]. In addition, subtherapeutic concentrations of drugs in vivo may be contributing to the selection of resistant parasites [3, 20, 21]. In the face of seemingly ineffective agents, societies are at risk of losing confidence in antimalarial medicines, their doctors and the healthcare system, and thus jeopardizing years of global public health success and investment [2].
\n
In many countries, inadequate laws and regulatory oversight, along with the lack of human, technical, and financial resources, do not encourage the manufacture and distribution of high-quality medicines [2, 22]. The WHO has estimated that nearly a third of countries lack the ability to oversee medicine manufacture, importation, or distribution [23]. With this in mind, the WHO is playing an important role in establishing quality standards for registration and quality control of antimalarials by a prequalification program [24]. Initiatives such as the African Medicine Registration Harmonization (AMRH), in which partners collaborate with the WHO, have also been started in an attempt to improve quality standards of medicines at local and regional levels [25]. In addition, pharmaceutical companies must be responsible for ensuring that the quality of antimalarials meets the stringent guidelines established by regulatory authorities, for testing their medicines accordingly and for releasing to market only medicines that pass these requirements [2, 22].
\n
This chapter will discuss the extent and consequences of poor-quality antimalarial medicines. In addition, the ways in which this issue might be tackled are also discussed, with a focus on the role of pharmaceutical companies, the WHO, and local and regional initiatives.
\n
\n
\n
2. Defining poor-quality antimalarials
\n
A variety of definitions have been used to classify the different types of poor-quality medicines [3, 26, 27]. The WHO has attempted to develop a consensus on definitions of poor-quality medicines, and has outlined two classes of drugs, namely those that are falsified, and those that are substandard [26].
\n
Falsified medicines have been fraudulently manufactured with fake packaging, and contain little or no active ingredient (and often other potentially harmful substances) [3, 26]. Falsified antimalarial tablets and ampoules containing little or no API are a major problem in some areas [25]. They may be impossible to distinguish from the genuine product and may lead to under-dosing and high levels of treatment failure. In some extreme cases, the falsified antimalarials may contain toxic ingredients [26].
\n
Substandard medicines have been poorly manufactured by a legitimate producer with no intent to deceive, but they usually have inadequate or excessive amounts of active ingredient(s) and/or excipients [3, 26]. The WHO also includes degraded drugs within this class [26]. The degraded drugs were originally of good quality, but become poor quality as a result of unsuitable or extended storage after manufacturing, or through interaction with inadequate excipients [3, 26].
\n
\n
\n
3. The growing problem of poor-quality antimalarials
\n
The problem of poor-quality antimalarial agents, particularly those containing artemisinins, is widespread and varies among countries. There are numerous reports of falsified and substandard antimalarial agents in particular in Africa and Asia [8–18].
\n
One WHO survey evaluated the quality of selected antimalarials in six countries in sub-Saharan Africa (Cameroon, Ethiopia, Ghana, Kenya, Nigeria, and United Republic of Tanzania) [8]. Samples were collected and tested for quality by reliable quality control laboratories according to specifications set up in recognized pharmacopeias. The researchers found that 28.7% of the 267 fully tested samples collected between April and June 2008 failed to comply with prespecified internationally acceptable quality criteria. A similar proportion of ACTs and sulfadoxine-pyrimethamine (SP) were subject to quality defects (29% for ACTs and 28% for SP; Figure 1). Prevailing problems associated with ACTs were related to the content of the APIs and the presence of impurities. For SP, it was mainly problems related to dissolution. Interestingly, only 4% of the drugs with the WHO prequalification status failed quality analysis, compared with 60% of drugs not prequalified by the WHO. Therefore, control of the quality of antimalarial medicines throughout the distribution system, according to proper specifications, is an important prerequisite for ensuring optimal treatment outcomes [8].
\n
In Southeast Asia, a similar problem with poor-quality medicines has been reported in a review of published and unpublished data from studies evaluating samples of antimalarials [3]. In seven Southeast Asian countries, 497 (35%) of 1437 samples failed chemical analysis, 423 (46%) of 919 samples failed packaging analysis, and 450 (36%) of 1260 samples were falsified [3]. The same review also found that, in sub-Saharan Africa (21 countries), 796 (35%) of 2297 samples failed chemical analysis, 28 (36%) of 77 samples failed packaging analysis, and 79 (20%) of 389 samples were falsified [3].
\n
Figure 1.
Proportions of compliant, moderately noncompliant and extremely noncompliant samples of artemisinin-based combination therapies (ACTs) and sulfadoxine-pyrimethamine (SP) in sub-Saharan Africa [8]. Extreme deviations were defined as a deviation by at least 20% from the declared content to one or more active ingredients, and/or dissolved percentage of one or more active ingredients less than the pharmacopoeial limit (Q) minus 25%.
\n
The World-Wide Antimalarial Resistance Network (WWARN) has developed a comprehensive, open-access, global database, with a linked Antimalarial Quality Surveyor (an online visualization tool) in order to more fully understand the evidence relating to poor-quality antimalarials [15]. A systematic literature search from 1946 to March 2013 identified 251 published antimalarial reports, of which 130 had sufficient information to estimate the frequency of poor-quality antimalarials [15]. Out of 9348 antimalarials sampled, 30.1% (2813) failed chemical or packaging quality tests. Of the 2813 failed samples, 39.3% were classified as falsified, 2.3% as substandard, and 58.3% as poor quality without evidence available to categorize them as either falsified or substandard. Oral artesunate was the medicine most commonly reported as falsified (with 61.9% failing). The survey found that 60.6% (63) of the 104 malaria-endemic countries had no publicly available reports on antimalarial drug quality. Further investigation of the quality of antimalarials is required in the Americas, and in central and southern African regions, as there have been very few studies conducted in these malarious areas [15].
\n
Studies from individual countries have also reported the existence of poor-quality antimalarials. One recent study used mystery shoppers and overt surveys to identify the quality of antimalarials in Cambodia [12]. Of 291 samples tested, 31.3% did not contain an appropriate amount of the API, i.e., the API content was not within the 85–115% range when measured by high performance liquid chromatography, and the samples were therefore considered to be of poor quality.
\n
A recent study of the quality of artemisinin-based antimalarials from Tanzania’s private sector found that, while none of the 1737 antimalarial samples were falsified, 4.1% were outside the 85–115% artemisinin API range [17]. WHO prequalified drugs (25.7% of the total) were more likely to be of higher quality, with only 0.5% WHO prequalified drugs being of poor quality, compared with 5.4% of those not WHO prequalified.
\n
\n
\n
4. Consequences of poor-quality antimalarials
\n
The use of poor-quality antimalarials has serious consequences (see Table 1) [3, 19, 28–36].
\n
\n
\n\n
\n
Increases in morbidity and mortality
\n
\n
\n
Financial loss for patients, healthcare system, pharmaceutical companies
\n
\n
\n
Loss of public confidence in pharmaceutical brand, medicines, pharmacies, and healthcare providers
\n
\n
\n
Increased drug resistance
\n
\n\n
Table 1.
Consequences of poor-quality antimalarials.
\n
\n
4.1. Morbidity and mortality
\n
Exposure to low-quality antimalarials results in poor treatment outcomes, with increased morbidity and mortality. The literature contains several case reports of patients placed at risk or dying as a result of poor-quality antimalarials [28–30]. A study in 39 sub-Saharan African countries estimated that approximately 122,350 (4%) of the deaths in children aged <5 years that occurred in 2013 were associated with poor-quality antimalarial agents [19].
\n
The impact of falsified and substandard medicines is likely to extend beyond such increases in morbidity and mortality. The continued use of poor-quality antimalarials that carry subtherapeutic levels of active ingredient will most likely lead to drug resistance [26, 31–36]. Partial artemisinin-resistant Plasmodium falciparum malaria has been reported in several Asian countries in the Greater Mekong Subregion [31–35]. The change in parasite sensitivity is manifest in the form of delayed parasite clearance, and has been associated with mutations in the Kelch 13 (K13) propeller region [37]. Indeed, the Greater Mekong Subregion is a major source from which drug-resistant malaria, including artemisinin-resistant P. falciparum, is known to emanate [38]. This occurs for multiple reasons, among which the local prevalence of falsified or substandard artemisinins is an important exacerbatory factor [38]. Based on the new WHO Global Technical Strategy for malaria 2016–2030, countries in the Greater Mekong Subregion have established a Strategy for Malaria Elimination in the Greater Mekong (2015–2030) in response to the threat of multidrug resistance in this region [36, 39]. The goals of the strategy are to eliminate P. falciparum malaria by 2025, and all malaria by 2030, in all countries in the Greater Mekong.
\n
\n
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4.2. Resistance
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Resistance can be prevented or its outset slowed by the use of combination antimalarials, with different mechanisms of action [26]. Consequently, the standard of care for uncomplicated P.falciparum (i.e. move P. from previous page to page 6, line 1 so as not to break P. falciparum (P. [space] falciparum)\n\n\n\n malaria is treatment with ACTs [26]. The use of artemisinin monotherapies in subtherapeutic doses for over 30 years and the availability of substandard artemisinins are thought to be a major driving force in the selection of the resistant phenotype in these regions [9, 10, 33]. Moreover, some therapies declared as combinations in effect have been proven to be artemisinin monotherapies [9]. Resistance to artemisinin compromises the efficacy of the ACT and adds pressure on the partner drug [26].
\n
Resistance to chloroquine has also been confirmed in Plasmodium vivax in 10 countries [36]. ACTs are now recommended for the treatment of chloroquine-resistant P. vivax, with the exception of treatment with artesunate and SP, where resistance to the partner drug may compromise the efficacy of the combination therapy.
\n
\n
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4.3. Economic burden
\n
The use of poor-quality antimalarials can have a negative financial impact on patients and their families [3, 16, 40]. Replacement or additional drugs, repeated courses of poor-quality antimalarials, repeated consultations at health facilities, and lost work days can all impose an unwanted economic burden [3, 16, 40], Indeed, recent modeling assuming current incidence rates of malaria indicates that widespread artemisinin resistance can be expected to lead to 116,000 excess deaths annually [41]. This burden may be particularly severe in some developing countries, where the majority of the population has to pay for their medicines and the cost of the medication represents a substantial proportion of the household income [40].
\n
Poor-quality antimalarials also have negative financial consequences for healthcare systems, pharmaceutical companies, governments and societies, and their use may potentially jeopardize the investments made in the past decades to control and eliminate malaria [3, 16, 40]. The lost productivity and increased healthcare costs associated with the use of poor-quality antimalarials generally occur in resource-constrained countries that are already disproportionately bearing the global cost of malaria [36, 40]. These countries generally lack the increased financial resources needed to inspect, analyze and police the antimalarial supply chain [7].
\n
In particular, the development and spread of resistance to antimalarial medicines has increased the cost of controlling malaria [36, 40, 41]. A decision-tree model estimated the direct medical costs for the effective treatment of malaria using ACT in nonresistant areas to be $US114 million (2013 costs). In comparison, it was estimated that these costs would increase by 28% if ACT was failing at a rate of 30%, and treatment of severe malaria reverted to quinine [41]. Productivity losses were estimated to be $US385 million for each year during which failing ACT was used as first-line therapy [41]. Most of this cost was associated with the lost productivity associated with excess morbidity after treatment had failed.
\n
The development of resistance to all current antimalarials would necessitate the development of new, and potentially more expensive, alternatives by pharmaceutical companies, further adding to the economic burden they incur when a poor-quality alternative is used instead of their legitimate high-quality product [40].
\n
If clinical trials use poor-quality medicines, not only are resources wasted, but patients may be harmed [42]. In addition, the erroneous conclusions reached in these trials may inappropriately inform public health policy [42].
\n
\n
\n
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5. Tackling the problem of poor-quality antimalarials
\n
A wide variety of issues have contributed to the proliferation of poor-quality medicines in developing countries (Table 2) [2, 3]. In order for the quality of antimalarials to be assured, these issues need to be addressed.
\n
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\n\n
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Inadequate testing of quality
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\n
\n
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Lack of inexpensive surveillance testing systems
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\n
\n
\n
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Lack of prequalified laboratories
\n
\n
\n
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Poor consumer and healthcare worker knowledge about product authenticity
\n
\n
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Inadequate standardization of procedures within quality surveys
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\n
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Self-prescription of drugs
\n
\n
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Availability of products via the Internet
\n
\n
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Expensive drugs with large profit margins
\n
\n
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Trading in free-trade zones or free ports with minimum regulation
\n
\n
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Poor or inadequate national, regional and global legislation, with few legal penalties
\n
\n
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Absence of drug regulatory authorities
\n
\n
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Unethical practices by manufacturers of antimalarials
\n
\n
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Lack of political will and cooperation from stakeholders
\n
\n
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Stockouts, thefts, and the erratic supply of antimalarials
\n
\n\n
Table 2.
Factors contributing to the manufacture and distribution of poor-quality antimalarials [2, 3, 16].
\n
It is essential that antimalarial medications be produced according to good manufacturing practice, contain the correct drug(s) and excipients in appropriate doses, and have bioavailability that is similar to the reference product; in addition, the drugs must be stored under appropriate conditions, and be dispensed before their expiry date [26].
\n
Some of the factors that contribute to the availability of poor-quality medicines can only be addressed by collaborative action between law enforcement bodies, regulatory authorities, and customs and excise agencies [26]. Encouragingly, some initiatives and mechanisms are already in place to help ensure that quality assured antimalarials are available for use in malaria-endemic countries.
\n
\n
5.1. Detection methods and technology
\n
Tests capable of accurately detecting and classifying poor-quality medicines at the point of entry into countries and at public and private pharmacies are essential for understanding the types, names, extent, and amount of poor-quality medicines being dispensed both nationally and globally [2, 7].
\n
Such tests can be conducted using quick, inexpensive methods in the field with the aim of examining packaging and detecting drug contents [7]. These tools would also empower those inspecting the medicines throughout the supply chain [7]. Rather than having to wait for the samples to be sent to national or international laboratories, results would be available more or less immediately [7]. Current methods for testing the quality of drugs in the field include visual packaging inspection, lot number reporting via mobile phones, thin-layer chromatography, colorimetric tests, and simplified spectroscopic methods [2, 7]. Portable instruments used to screen for the quality of antimalarial agents include Raman spectrometers and the Global Pharma Health Fund GPHF-Minilab® [40]. Other simple, technologies for testing the quality of antimalarials in the field are in development [43, 44].
\n
More accurate methods of testing the quality of medicines involve laboratories that are equipped for exhaustive chemical analysis [2]. Such investigations can be difficult in developing countries, given the sophisticated and expensive equipment, the type of reagents, and the level of technical expertise that are required. For example, Kenya, Tanzania, South Africa, and Uganda are currently the only countries in Africa with WHO prequalified laboratories for drug quality testing [19, 45].
\n
\n
\n
5.2. Field reports
\n
Quality surveys can serve as an important source of information about the quality of medicines available. Data on the quality of antimalarials, if properly collected, interpreted and used, are essential for the planning of effective interventions [46]. However, reports that have not employed rigorous scientific techniques will potentially bias results [47]. To ensure consistency and accuracy, the WHO has recently produced draft guidelines for the conduct of surveys of quality medicines [46].
\n
\n
\n
5.3. Legislation and regulation
\n
Existing laws in many countries are insufficiently strict to deter the manufacturing and distribution of poor-quality medicines; where this legislation exists, it may not be implemented [22]. Such absence of legislation prohibiting the manufacture and distribution of poor-quality medicines encourages their continued manufacturer, since there is no fear of being apprehended and prosecuted [2, 22].
\n
Appropriate national medicine regulatory authorities would help to ensure that all pharmaceutical products on the market were safe, effective and meet approved quality standards [48]. Such regulation would control registration and postmarketing surveillance (quality monitoring and pharmacovigilance) of medicines, as well as the licensing and inspection of manufacturers, importers, exporters, wholesalers, distributors, pharmacies and retail outlets, control of clinical trials, and control of the promotion (Figure 2) [48]. It has also been suggested that an international legal convention against poor-quality medicines would address both regulatory and criminal international governance challenges [7].
\n
Figure 2.
Regulatory system for medicines [48]. GCP, good clinical practices; GDP, good distribution practices; GLP, good laboratory practices; GMP, good manufacturing practices; GPP, good pharmaceutical practices; GSP, good storage practices.
\n
However, the WHO has estimated that 30% of member countries lack any capacity to oversee medicine manufacture, importation, or distribution [23]. At present, only about 20% of member countries have well-developed medicine regulation at varying levels of development and operational capacity.
\n
In particular, the lack of global harmonization of drug registration processes is contributing to the increased availability of poor-quality antimalarials. Regulatory authorities such as the European Medicines Agency (EMA) and the United States Food and Drug Administration (FDA) provide guidelines for the registration of new drugs for the pharmaceutical industry. Such guidelines include steps for assuring drug quality [49, 50]. For example, the FDA regulates and controls new drugs according to the new drug application process and the review and ultimate approval of generic drugs is controlled by regulations for abbreviated new drug applications.
\n
However, similar rigorous standards are not applied universally, and particularly in sub-Saharan Africa. Africa currently has more than 50 independent local regulatory health authority agencies, with different administrative and technical requirements, processes and timelines for medicine registration and regulatory review, and with variable transparency of the registration process. A recent WHO assessment in 26 sub-Saharan African countries found that drug approval regulation was not carried out to the extent required to ensure the quality, efficacy, and safety of medicines [48]. Few countries in sub-Saharan Africa relied on the decisions made by other regulators, such as those stringently applied by the EMA or FDA, or by the WHO through its Prequalification of Medicines Program [48].
\n
\n
\n
5.4. The role of the WHO
\n
Many look to the WHO for leadership in regulating the quality of medicines, especially in light of its successful implementation of the public health treaty on tobacco control [7].
\n
Due to the association of oral artemisinin monotherapies with the development of resistance, the WHO urges regulatory authorities in malaria-endemic countries “to take measures to halt the production and marketing of these oral monotherapies, and promote access to quality-assured artemisinin-based combination therapies” [51]. The number of countries that allow the marketing of oral artemisinin monotherapies has dropped markedly since the World Health Assembly adopted a resolution supporting the ban in 2007. As of November 2015, marketing of artemisinin monotherapies was still allowed by seven countries: Angola, Cape Verde, Colombia, Gambia, Sao Tome and Principe, Somalia, and Swaziland [51]. However, a continued strengthening of pharmaceutical regulation and the enforcement of existing regulations will be required for the complete withdrawal of oral artemisinin monotherapies from all countries.
\n
In an attempt to standardize the quality of medicines that reach the market, in terms of their efficacy, safety, and method of manufacture, the WHO are managing the Prequalification of Medicines Program [24]. This program’s quality evaluation criteria are based on international pharmaceutical standards and a mix of the best practices applied by the world’s leading regulatory authorities [52]. Products that meet all of the criteria of the WHO Prequalification of Medicines Program are considered to be quality assured and are added to a WHO list of prequalified medicinal products [53]. This list is used by international procurement agencies and by countries to guide bulk purchasing of medicines. Currently, over 40 of the prequalified medicinal products on this list are antimalarial agents [53]. This program has validated the entry of a number of generic products into markets and procurement pools [52]. Such validation has provided an incentive for other manufacturers of generic products to raise their quality standards and increase the availability of affordable medicines.
\n
In addition to prequalifying medicines, this program also prequalifies pharmaceutical quality control laboratories and active pharmaceutical ingredients, as well as advocating for medicines of guaranteed quality [24].
\n
\n
\n
5.5. The AMRH initiative
\n
One of the means of improving quality standards is to engage regional networks in developing countries with larger, more powerful and better resourced organizations such as the WHO. One example of such a network is the African Medicine Registration Harmonization Initiative (AMRH) [25, 54]. This program aims to harmonize the registration of medicinal products in Africa across regional economic communities (RECs) [25, 54]. In Africa, the RECs range in size from five to more than twenty‐five member states—and all have been invited to participate in the AMRH program.
\n
Partners involved in the AMRH program include the WHO, the New Partnership for Africa’s Development, the African Union Commission, the Pan-African Parliament, the World Bank, the Bill and Melinda Gates Foundation, the UK Department for International Development, and the Clinton Health Access Initiative [25]. The WHO is to provide leadership for the development of common technical standards, documents, tools, and processes in line with international standards. The WHO also provides technical assistance for capacity-building and organizes joint assessment and inspection activities [25].
\n
The first REC to secure funding from the AMRH initiative trust fund was the East African Community (EAC). The EAC Medicines Registration Harmonization (MRH) project was formally launched in 2012 in Tanzania and aims to achieve a harmonized medicines registration process in its member countries (Uganda, Kenya, the United Republic of Tanzania, Rwanda, and Burundi) based on common documents, processes, and shared information [25]. Given the progress made in the EAC MRH project, the AMRH initiative plans to expand to other RECs in Africa. It is hoped that five or six groupings will eventually cover the entire African continent. Continued support by concerned governments and international partners will be crucial for its success [25].
\n
\n
\n
5.6. The role of pharmaceutical companies
\n
Poor manufacturing and quality-control practices in the production of genuine drugs (either branded or generic) have considerable impact on the quality of medicines [40]. Pharmaceutical companies are responsible for ensuring that quality meets the guidelines of stringent health authorities, for testing their medicines accordingly and for releasing only medicines that pass these requirements [55]. Chinese and Indian manufacturers are commonly cited as sources of poor-quality antimalarials, but manufacturers in other countries may also be involved [7, 40]. It is essential that pharmaceutical companies behave ethically at all times and follow relevant guidelines and codes of conduct provided by regulatory authorities if the quality of medicines is to be assured.
\n
Reputable pharmaceutical companies must ensure that medicines are under strict surveillance, and with quality control measures in place at all stages of the drug supply chain. Novartis, for example, ensures the quality control of medicines in a three-step process that involves verification, authentication, and pharmaceutical forensic investigations. Verification occurs at the local level to attest to the genuineness of the packaging materials and the plausibility of the manufacturing data (batch number, manufacturing, and expiry date). Authentication, done in the field, involves analyzing the product (tablets, liquids) with vibrational spectrometers. In the case of substantiation of falsification of medicines, a pharmaceutical forensic investigation then occurs, and any substantiated falsification incidents are escalated to the key stakeholders and national health authorities and the WHO are notified.
\n
Figure 3.
Process for review and approval of generic drugs (ANDA) [58]. Source: US Food and Drug Administration (public domain).
\n
In countries where stringent regulatory authorities exist, pharmaceutical companies developing new drugs must follow a new drug application process that requires both preclinical and clinical studies [50]. In contrast, the approval of generic drugs or new formulations of existing drugs occurs via an abbreviated process that does not require clinical efficacy and safety studies (Figure 3) [56]. One of the dangers with some generic products is that they may contain the correct amounts of the drug, but, because of their formulation, they are not adequately absorbed, resulting in lower efficacy. Consequently, this abbreviated process requires proof that the generic product (or new formulation of a reference product) and the reference product have comparable bioavailability. If this is established, the products are said to be bioequivalent [56, 57].
\n\n
Different types of evidence may be used to establish bioequivalence for pharmaceutically equivalent drug products, including in vivo or in vitro testing, or both [56]. If a generic product or new formulation shows equivalent exposure to the original marketed compound, it is assumed that its efficacy and safety will also be equivalent [56]. To this end, the WHO recommended that not only must all antimalarial medicines be manufactured according to good manufacturing practice and have the correct drug and excipient content, but they must also be proven to have bioavailability that is comparable to that of the reference listed product [26].
\n
An example of a study that was conducted in line with these bioequivalence guidelines involves the antimalarial artemether-lumefantrine [58]. Because development of this compound adhered to these guidelines, this formulation received the WHO prequalification status in June 2014 [53]. The novel fixed-dose tablet formulation of the antimalarial artemether-lumefantrine 80/480 mg was developed in order to reduce the pill burden at each dose and potentially enhance adherence. It was then tested in a bioequivalence study in healthy volunteers against four standard tablets of artemether-lumefantrine 20/120 [59]. Bioequivalence between the two formulations was established, with the prespecified criteria for bioequivalence being met. These prespecified criteria were that the 90% confidence intervals for the geometric mean ratio (novel formulation versus four standard tablets) of the primary pharmacokinetic endpoints (AUC and Cmax) for artemether and lumefantrine were contained within the acceptance interval of 0.80–1.25. These outcomes established that the rate and extent of absorption of both components of the ACT in the novel formulation of artemether-lumefantrine are comparable to those in the standard tablets.
\n
\n
\n
\n
6. Conclusion
\n
There is a pressing need to reduce the use of poor-quality antimalarial medicines, especially in Africa and Asia. The problem is driven by several factors, including a lack of national and international drug legislation, and inadequate quality assurance by some pharmaceutical companies. This chapter has reviewed the steps and studies needed to ensure development of high-quality medicines based on health authority regulations (including WHO prequalification). The problem of poor-quality medicines can only be addressed by a multipronged approach that includes tackling poor regulation and ineffective/poorly implemented laws at national and international levels. Sustained national and international financing must underpin any such future approach. A legal framework or treaty that protects all countries against poor-quality medicines is also urgently required. Such a framework would facilitate the production of high-quality antimalarials and protect all countries against those who produce, distribute, and sell poor-quality products. In addition, pharmaceutical companies must be responsible for ensuring that the quality of antimalarials meets the stringent guidelines established by regulatory authorities, for testing their medicines accordingly and for releasing only medicines that pass these requirements into the market. The harmonization of the registration process across all nations would help ensure that patients throughout the world obtain access to high-quality antimalarials.
\n
Surveillance of the quality of antimalarials is an essential component of the global fight against malaria. The establishment of a highly qualified, well-resourced international organization that works in collaboration with national medical regulatory bodies, pharmaceutical companies, and international agencies may help to ensure access to high-quality antimalarials on a global level. The implementation of strategies such as the WHO Prequalification Program, the AMRH initiative, and the ethical production of medicines by pharmaceutical companies will help to ensure that antimalarial therapies marketed in low-income, malaria-endemic countries are quality assured. Future research must focus on innovative technologies that accurately and affordably support the detection of poor-quality medicines at all levels of the supply chain, including prequalified reference laboratories. It is to be hoped that the implementation of such a multipronged approach by policy makers and leaders at the international and national levels will ensure the continued global availability of affordable, high-quality drugs to patients with malaria.
\n
\n
Acknowledgments
\n
KH is an employee of Novartis Pharmaceuticals Corporation and KS is an employee of Novartis Pharma AG.
\n
\n',keywords:"antimalarial medicines, malaria, quality, Africa, Asia",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/51663.pdf",chapterXML:"https://mts.intechopen.com/source/xml/51663.xml",downloadPdfUrl:"/chapter/pdf-download/51663",previewPdfUrl:"/chapter/pdf-preview/51663",totalDownloads:1239,totalViews:285,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:0,dateSubmitted:"December 21st 2015",dateReviewed:"June 21st 2016",datePrePublished:null,datePublished:"November 30th 2016",dateFinished:null,readingETA:"0",abstract:"The use of poor-quality antimalarials has devastating consequences, including increased morbidity, mortality, and drug resistance. Unfortunately, this issue appears to be widespread, especially in parts of Africa and Asia, jeopardizing the progress and investments already made in global malaria control in these regions. In developing countries, inadequate laws and regulatory oversight, along with the lack of human, technical, and financial resources, do not encourage the manufacture and distribution of high-quality medicines. The problem of poor-quality medicines can only be addressed by a multipronged approach that includes tackling poor regulation and ineffective/poorly implemented laws at national and international levels. In addition, pharmaceutical companies must be responsible for ensuring that the quality of antimalarials meets the stringent guidelines established by regulatory authorities, for testing their medicines accordingly and for releasing to market only medicines that pass these requirements. The chapter also discusses how the implementation of strategies such as the WHO Prequalification Program, the African Medicine Registration Harmonization initiative, and the ethical production of medicines by pharmaceutical companies help to ensure that antimalarial therapies marketed in low-income, malaria-endemic countries are quality assured.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/51663",risUrl:"/chapter/ris/51663",book:{slug:"current-topics-in-malaria"},signatures:"Kamal Hamed and Kirstin Stricker",authors:[{id:"184106",title:"Dr.",name:"Kamal",middleName:null,surname:"Hamed",fullName:"Kamal Hamed",slug:"kamal-hamed",email:"kamal.hamed@novartis.com",position:null,institution:null},{id:"187758",title:"Dr.",name:"Kirstin",middleName:null,surname:"Stricker",fullName:"Kirstin Stricker",slug:"kirstin-stricker",email:"kirstin.stricker@novartis.com",position:null,institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Defining poor-quality antimalarials",level:"1"},{id:"sec_3",title:"3. The growing problem of poor-quality antimalarials",level:"1"},{id:"sec_4",title:"4. Consequences of poor-quality antimalarials",level:"1"},{id:"sec_4_2",title:"4.1. Morbidity and mortality",level:"2"},{id:"sec_5_2",title:"4.2. Resistance",level:"2"},{id:"sec_6_2",title:"4.3. Economic burden",level:"2"},{id:"sec_8",title:"5. Tackling the problem of poor-quality antimalarials",level:"1"},{id:"sec_8_2",title:"5.1. Detection methods and technology",level:"2"},{id:"sec_9_2",title:"5.2. Field reports",level:"2"},{id:"sec_10_2",title:"5.3. Legislation and regulation",level:"2"},{id:"sec_11_2",title:"5.4. The role of the WHO",level:"2"},{id:"sec_12_2",title:"5.5. The AMRH initiative",level:"2"},{id:"sec_13_2",title:"5.6. The role of pharmaceutical companies",level:"2"},{id:"sec_15",title:"6. Conclusion",level:"1"},{id:"sec_16",title:"Acknowledgments",level:"1"}],chapterReferences:[{id:"B1",body:'\nHamburg M. 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Malar J. 2014;13:452.\n'},{id:"B42",body:'\nNewton PN, Schellenberg D, Ashley EA, Ravinetto R, Green MD, ter Kuile FO, et al. Quality assurance of drugs used in clinical trials: proposal for adapting guidelines. BMJ. 2015;350:h602.\n'},{id:"B43",body:'\nWeaver AA, Lieberman M. Paper test cards for presumptive testing of very low quality antimalarial medications. Am J Trop Med Hyg. 2015;92(6 Suppl.):17.\n'},{id:"B44",body:'\nHo NT, Desai D, Zaman MH. Rapid and specific drug quality testing assay for artemisinin and its derivatives using a luminescent reaction and novel microfluidic technology. Am J Trop Med Hyg. 2015;92(6 Suppl.):24.\n'},{id:"B45",body:'\nWorld Health Organization. WHO list of prequalified quality control laboratories. 38th edition, 2016. Available from: www.who.int/prequal/lists/PQ_QCLabsList.pdf [Accessed: February 22, 2016].\n'},{id:"B46",body:'\nWorld Health Organization. Guidelines on the conduct of surveys of the quality of medicines: draft for comment. 2016. Available from: http://www.who.int/medicines/areas/quality_safety/quality_assurance/Guidelines-on-medicines-quality-surveys-QAS15-630_30062015.pdf. [Accessed: July 7, 2016].\n'},{id:"B47",body:'\nNewton PN, Lee SJ, Goodman C, Fernandez FM, Yeung S, Phanouvong S, et al. Guidelines for field surveys of the quality of medicines: a proposal. PLoS Med. 2009;6(3):e52.\n'},{id:"B48",body:'\nWorld Health Organization. Assessment of medicines regulatory systems in sub-Saharan African countries. 2010. Available from: www.who.int/healthsystems/Assessment26African_countries.pdf?ua=1. [Accessed: July 7, 2016].\n'},{id:"B49",body:'\nEuropean Medicines Agency. EMA Scientific Guidelines. 2015. Available from: http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000043.jsp&mid=WC0b01ac05800240cb [Accessed: July 7, 2016].\n'},{id:"B50",body:'\nUnited States Food and Drug Administration. FDA drug development guidelines. 2015. Available from: http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/InvestigationalNewDrugINDApplication/ucm176522.htm. [Accessed: July 7, 2016].\n'},{id:"B51",body:'\nWorld Health Organization. Withdrawal of oral artemisin-based monotherapies. 2016. Available from: http://www.who.int/malaria/areas/treatment/withdrawal_of_oral_artemisinin_based_monotherapies/en/. [Accessed: July 7, 2016].\n'},{id:"B52",body:'\nWorld Health Organization. Improving quality for better treatment and greater access: prequalifications of medicine programme. 2012. Available from: http://apps.who.int/prequal/info_general/documents/advocacy/Advocacy_booklet_2012.pdf. [Accessed: July 7, 2016].\n'},{id:"B53",body:'\nWorld Health Organization. WHO list of prequalified medicinal products. 2016. Available from: http://apps.who.int/prequal/. [Accessed: July 7, 2016].\n'},{id:"B54",body:'\nWorld Health Organization. WHO support for medicines regulatory harmonization in Africa: focus on East African Community. 2014. Available from: http://www.who.int/medicines/publications/druginformation/DI_28-1_Africa.pdf. [Accessed: July 7, 2016].\n'},{id:"B55",body:'\nWorld Medical Association. WMA Declaration of Helsinki—Ethical Principles for Medical Research Involving Human Subjects. 2016. Available from: http://www.wma.net/en/30publications/10policies/b3/. [Accessed: July 7, 2016].\n'},{id:"B56",body:'\nUnited States Food and Drug Administration. Product-specific recommendations for generic drug development. 2016. Available from: http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm075207.htm. [Accessed: July 7, 2016].\n'},{id:"B57",body:'\nEuropean Medicines Agency. Guideline on the investigation of bioequivalence. 2015. Available from: www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/01/WC500070039.pdf. [Accessed: July 7, 2016].\n'},{id:"B58",body:'\nUnited States Food and Drug Administration. The FDA Process for Approving Generic Drugs. 2007. Available from: http://www.fda.gov/Training/ForHealthProfessionals/ucm090320.htm. [Accessed: July 7, 2016].\n'},{id:"B59",body:'\nLefevre G, Bhad P, Jain JP, Kalluri S, Cheng Y, Dave H, et al. Evaluation of two novel tablet formulations of artemether-lumefantrine (Coartem) for bioequivalence in a randomized, open-label, two-period study. Malar J. 2013;12:312.\n'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Kamal Hamed",address:"kamal.hamed@novartis.com",affiliation:'
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1. Introduction
1.1 Anatomy
Proprioception was first described by Sir Charles Bell in 1830s as sixth sense coming from Latin word proprius meaning “one’s own” and perception “perceiving one’s own self” [1]. Proprioception is generally defined as either the sense of position or the motion of the limbs and body in the absence of vision [2]. Limb position is a static sense, whereas limb motion is a dynamic sense [3]. It is described as the most important sensorial modality for the internal representation of body map providing static and dynamic proprioceptive systems [4].
Proprioception is a complex system having both conscious and unconscious components involving peripheral and central pathways. The proprioceptive sensations arise from the deeper tissues. The main receptors are muscle spindles, tendons, Ruffini endings in joint capsules ligaments and Pacinian corpuscles reacting pressure, tension, stretching or contraction. The cutaneous receptors of the skin also contribute to joint position and motion sense especially at digits, elbow and knee. The term kinesthesia is generally used to describe the conscious awareness of the body or limb position in space [1, 5, 6, 7]. Conscious proprioceptive impulses elongate along large and myelinated fibers from the peripheral nerves into the dorsal root ganglion of spinal cord (first order neurons) and then via the medial division of the posterior root, via posterior white columns of fasciculi gracilis and cuneatus and ascend to the nuclei gracilis and cuneatus in the lower medulla. Axons of the second-order neuron decussate as internal arcuate fibers (second order neurons), and then ascend in the medial lemniscus to the contralateral somatosensory region of thalamus (Figure 1) [2, 5].
The main pathway for proprioceptive information is via the dorsal column medial lemniscal, posterior and anterior spinocerebellar tracts and spinoreticular tracts [6, 7].
There is a high density of complex spindles in deeper cervical muscles particularly in the intermediate columns, acting as neck prorioceptive receptors. This system is important for head and neck position sense together with the high density muscle spindles of sub-occipital triange. The density of muscle spindles is higher in the upper cervical spine when compared with the lower cervial and cervico-thoracic and thoraco-lumbar junctions [8]. Neck proprioception plays an important role in limb coordination and body-scheme representation [8]. Proprioceptive impulses from the head and neck are supplied by cranial nerves [5].
Contralateral primary and secondary sensorimotor cortex, supplementary motor area and bilateral inferior parietal lobes and basal ganglia (especially nigrostriatal pathways, striatal neurons and putamen) are involved in processing proprioceptive information during passive movement [9, 10]. The cerebellum contributes to proprioception only during movement [3]. Especially deep medial fastigial nucleus of cerebellum converges vestibular and neck proprioceptive sensory signals describing body’s movement in space [11, 12].
1.2 Proprioception and motor control
The sensorimotor system, defined as the sensory, motor, and central integration, is a crucial and intricate component of the motor control system [13]. Motor control is a complex and dynamic process based on the selective integration of sensory information from multiple sources, motor commands, and motor output [13, 14]. There are specific unique roles associated with each sensory source (i.e., somatosensory, visual, vestibular) that cannot be compensated fully with each other [14, 15]. The environment is experienced through sensory systems: exteroception (e.g., sight, hearing, touch), interoception (e.g., arousal, pain, visceral sensations, muscular sensations), and proprioception (e.g., sense of position, motion, and force), which all required for successful motor control [16, 17]. During a task-oriented activity, motor adaptation, defined as a process of modifying the movement based on error feedback [18], skills are needed to cope with the changes occurring in the external and internal environment [2]. Motor adaptation is stimulated with sensorial triggers by using both feedback (reactive: adjust ongoing motor behavior) and feedforward (preparatory: pre-planning and anticipating the motor sequence from the previous experience) mechanism. Proprioceptive information, from proprioceptors found in muscle, tendon, ligament, capsule, skin, and fascial layers, plays an integral role in motor control and considered as multifold [14].
The role of proprioceptive information in motor control can be divided into two categories: external environment (even vs. uneven ground) and internal environment (carrying a load on shoulders vs. hands below knuckle height). The motor programs often need to be adjusted to accommodate unexpected perturbations or changes in the external environment. Although the source of this information is usually associated mainly with visual input, there are many situations where proprioceptive input is the fastest and/or most accurate. Proprioception is necessary during motion execution to update feedforward commands derived from the visual image [14]. Attention to environmental constraints is also required because dealing with complex environments often requires behavioral flexibility to maintain postural balance [19]. Secondly, the central nervous system needs an updated body schema of the biomechanical and spatial properties of body parts to plan and modify internally generated motor commands [20]. Before and during a motor command, the motor control system must consider the current and changing positions of the respective joints to account for the complex mechanical interactions within the musculoskeletal system components [14] . Additionally, proprioception is important after movement to compare the actual movement and intended movement, besides the predicted movement derived from the efference copies (corollary discharge: copying of motor commands based on past events) of motor commands, which has an essential role in motor learning to update the internal forward model of motor command [21].
1.3 Proprioception and postural control
During the execution of all motor tasks, proprioception is required to prepare, maintain, and restore the stability of both the entire body (postural equilibrium) and the segments (joint stability) [14, 15]. Postural control, defined as controlling the position of the body regarding the task in the environment, involves neural control of “postural equilibrium” and “postural orientation”. Postural equilibrium consists of the coordination of sensory and motor strategies to maintain balance by controlling the body’s center of mass (COM) over its base of support (BOS) to maintain postural stability during both intrinsic (self-initiated) and extrinsic (externally triggered) disturbances. The postural equilibrium controls stability during both static (i.e., quiet standing) and dynamic (i.e., walking and reaching) situations. Postural orientation involves positioning body alignment with respect to gravity, the support surface, visual environment, and other sensory reference frames [22].
Postural control is considered as a complex motor skill derived from the interaction of multiple sensorimotor processes, which are; biomechanical constraints (i.e., BOS, degrees of freedom, strength, limits of stability), movement strategies (i.e., reactive, anticipatory, voluntary), sensory strategies (i.e., sensory integration, sensory re-weighting), orientation in space (i.e., perception of visional verticality, perception of postural verticality), control of dynamics (i.e., gait, proactive), cognitive processing (i.e., attention, learning, reaction time), experience and practice [23]. Impairment of the proprioceptive sensation can disrupt any of these six resources, which contributes to postural control (Figure 2). “Sensory strategies” are one of the most critical issues to discuss. Sensory information from somatosensory (tactile sense and proprioception), visual and vestibular systems must be integrated to interpret complex sensory environments for achieving postural control. Depending on the environmental conditions, the relative contribution of each sensory system changes, which is referred to as “sensory re-weighting” [24]. Healthy persons rely on somatosensory (70%), vision (10%), and vestibular (20%) information when standing on a stable surface in a well-lit environment (13). On the other hand, when standing on an unstable surface, due to decreased dependence on surface somatosensory inputs for postural orientation, they need to increase sensory weighting to vestibular and visual information [25]. The dynamic regulation or re-weighting of sensory cues is essential for maintaining postural stability when moving between different environments requiring distinct sensorial systems, such as different surfaces (i.e., walking on the sidewalk, walking on grass) or different lighting (i.e., moving in a well-lit room, moving in a dark room) [23]. The interplay between these three sensory modalities is critical for accurate estimates of self-motion and postural control [26].
Figure 1.
Neuroanatomic pathway adopted from DeJong’s the neurologic examination.
Besides different sensory cues, different mechanical conditions provide significant advantages to humans for maintaining upright standing [27]. Decreased proprioception could lead to “biomechanical constraints” such as abnormal joint biomechanics and decreased muscle strength [28, 29], leading to postural dyscontrol. The “control of dynamics” is defined as the ability to perceive body segments relative to one another to stabilize the COM. Maintaining COM requires input from multiple sensory systems, sensorial re-weighting, and multisensory integration to calculate body state, including the COM and heading [30]. “Movement strategies” (i.e., postural sway, ankle strategy, hip strategy) can be used to return the body to equilibrium in a stance position [23]. Without proprioceptive input from the ankle and knee, ankle muscle responses are delayed suggesting that lower leg balance correcting responses are triggered by hip and, possibly, trunk proprioceptive inputs. Especially hip muscle proprioceptive inputs, considered critical for automatic balance correcting responses [31]. Additionally, cervical proprioception is of particular importance for “orientation in space”. Neck muscle inflow has effects on the perception of body orientation and motion. Prolonged, intense proprioceptive input from neck muscles can induce persistent influences on self-motion perception and cognitive body representation [32]. The loss of proprioception could also impact the “cognitive processing” specifically the reaction time, and other factors such as attention, memory, and visuospatial abilities may contribute to spatial cognitive skills (Figure 2) [23].
Figure 2.
Adapted from the framework of the six important resources required for postural control system by Horak, 2006 [23], the contribution of proprioception sensation to postural control.
2. Clinical implications and evaluation of proprioception
The loss of proprioceptive afferents may affect the control of muscle tone, disrupts postural reflexes, and severely impairs spatial and temporal aspects of movement [33]. Proprioceptive impairments are associated with various neurological conditions such as stroke [34], Parkinson’s disease [35], peripheral neuropathy [36], as well as orthopedic conditions such as low back pain [37], neck pain [38], sports injuries like chronic ankle instability [39], ACL injuries [40], post-operatively such as mastectomy [41], knee arthroplasty [42], and aging [43]. Considering the importance of proprioception for motor control, a detailed evaluation of proprioceptive sense and application of treatment approaches focusing on training the proprioceptive sense is important for restoring motor function. Proprioception can be measured by using specific and non-specific tests in clinical practice.
Specific Tests of Proprioception: assess an individual’s status regarding the joint position sense and kinesthesia [21]. Joint position sense tests assess precision or accuracy in repositioning the joint at a predetermined target angle and can be measured as active joint position detection (AJPD) [e.g., position matching task, position copying task] and passive joint position detection (PJPD) [e.g., thumb finding test, dual-joint position test] [44]. Kinesthesia tests assess the ability to perceive joint movement. For evaluating the perceptual aspect of proprioception, psychophysical thresholds represent the gold standard [33]. These tests are usually performed passively and can be measured by using passive motion detection threshold (PMDT) and passive motion direction discrimination (PMDD) [e.g., distal proprioception test, Rivermead Assessment of Somatosensory Perception] [44].
Non-specific Tests of Proprioception: for determining the contribution of proprioceptive signals on balance control, functional balance tests can be used to provide an estimate of potential proprioceptive disturbances [33]. These tests involve all body and other sensory and motor functions; therefore, they are considered non-specific tests of proprioception [21]. Balance tests can be modified to challenge proprioception, such as unilateral/bilateral stance with eyes open/closed, different supporting surfaces (i.e., stable or unstable), and with/without perturbations [44, 45]. Stereognosis and skilled motor function tests are important as they indicate the contribution of proprioceptive system in the performance of many activities of daily living [46].
3. Neurologic correlation
The complexity of sensorimotor systems requires deep knowledge of anatomy and physiology to analyze and localize the symptoms and the signs of the patients. Joint sense and vibration sense examination is an important component of neurological examination.
The classic diseases causing sensory ataxia are tabes dorsalis, polyneuropathies (especially involving large fibers), dorsal root ganglionopathies and subacute combined degeneration. With parietal lobe lesion, position sense is often impaired and vibration preserved [5]. Vibratory sensation may also be impaired in lesions of the peripheral nerves, plexopathies, radiculopathies, dorsal root ganglion, posterior columns and medial lemniscus. In patients with peripheral neuropathies, vibration sensation is lost in the lower extremities first. Impaired vibration from posterior column disease is more likely to be uniform at all sites in the involved extremities. In spinal cord diseases, detecting a “level” of vibration sensory (segmental demarcation) loss over the spinous processes is crucial for diagnosis [5]. In patients with diabetic neuropathy, the decline in proprioceptive function may be caused by impairment in muscle spindle function and or the spindle receptors itself [47].
In patients with hereditary sensory and autonomic neuropathy type III patients (Riley-Day Syndrome, familial dysautonomia) ataxic gait is explained by poor proprioceptive acuity at the knee joint [48]. In mitochondrial ataxias sensory ataxia (which classically include gait ataxia worsened by loss of visual fixation) is due to the involvement of proprioception, secondary to peripheral neuropathy or neuronopathy [49]. In patients following whiplash type injuries involving soft tissues of cervical spine leads to proprioceptive deficits affecting head and position sense. Also in patients with chronic whiplash associated disorders are reported to have balance and dizziness problems, head and eye movement impairments reflecting mismatch od afferent input from the proprioceptive, visual and vestibular systems [8, 50]. Lesions of the dorsal columns impairs sensation of touch, vibration and proprioception in the ipsilateral side of the body below the injury level [51]. In patients with non-specific low back pain, postural control is impaired during standing and slow performance movements. This is due to an altered use of ankle compared to back proprioception related activity in right primary motor cortex and frontoparietal cortex [52]. Brainstem lesions resemble those in spinal cord disease as it selectively involves spinothalamic tract or medial lemniscus causing contralateral loss of position sense and vibration sense [5].
Neglect is a condition in which patients loose self-spatial awareness opposite to the damaged site of the brain. It is proposed that it is associated with the lesions of the dorsal stream causing dysfunction of proprioceptive space which is encoded in the bilateral parietal cortex [53]. Loss in the position sense may cause pseudochoreoathetosis as well. This abnormal involuntary, spontaneous movements are restricted to the parts with proprioceptive sensory loss. It is proposed that failure to integrate cortical proprioceptive sensory inputs in striatum may explain this situation [5, 54].
There are experimental evidence of proprioception impairments in Parkinson’s disease. Parkinsonian gait is affected by the involvement of lower limb proprioceptive deficits as well as the involvement contralateral somatosensory and premotor lateral cortices and posterior cingulate cortex and basal ganglia and bilateral prefrontal cortex [10, 55, 56]. It was also shown that conscious perception of kinaesthetic stimuli is impaired in Parkinson’s disease as cerebro-basal loops are not intact [9].
Weeks and colleagues showed that patients with cerebellar damage had reduced dynamic proprioceptive acuity which was also parallel to their motor deficits [3]. Diseases of the primary somatosensory cortex do not generally produce sensory symptoms but deteriorate fine and delicate manipulations in the contralateral part depending on position sense [2, 5]. Many patients with stroke experience proprioceptive deficits. Recovery of proprioception increases in the chronic phase [57, 58]. In study by Pope it was shown that proprioceptive input from the neck also may change cerebellar output affecting M1 plasticity [59]. In the study of Vidoni and colleagues preserved motor learning after stroke was related to the degree of proprioceptive deficit suggesting the relation between proprioceptive perception from muscle spindles and motor learning and central neuroplasticity [58, 60].
4. Proprioception after orthopedic surgeries
Studies on changes in joint proprioception after orthopedic surgeries are available in the literature. This section consists of the information in the literature about our five major joints.
4.1 Knee joint
Knee proprioception is necessary to achieve normal joint coordination during movement as well as providing joint stabilization [61, 62]. The anterior cruciate ligament (ACL), posterior cruciate ligament, collateral ligaments and menisci contribute to proprioception with the help of proprioceptors they have [63, 64]. The mechanoreceptors of the cruciate ligaments, together with the mechanoreceptors of the joint capsule, transmit information about the extension and flexion of the knee joint to the brain [65].
The ACL is the most important ligament involved in knee mechanical and neuromuscular stability. It contributes to proprioception in joint movement. However, the ACL is the most frequently injured ligament. After ACL rupture, knee proprioception is disrupted [66, 67].
Various autografts and allografts are used for ACL reconstruction. Patellar tendon or hamstring tendons may be preferred in patients using autografts. In addition, different techniques and materials are used. However, there is no gold standard in graft and technique selection [68]. In order for ACL reconstruction to be successful, not only mechanical but also neuromuscular stability is required. Neuromuscular stability depends on obtaining proprioception [69]. ACL injury leads to degradation of mechanoreceptors and a histologic study revealed that free nerve endings disappear after 1 year [70]. The effectiveness of ACL reconstruction in regaining proprioception has been tried to be revealed by some studies [71, 72, 73, 74]. While some studies argue that ACL reconstruction is not sufficient to restore joint position [71, 72, 73], some studies advocate the adverse opinion [74]. The lack of a test to distinguish about whether the proprioception is derived from the soft tissues around the knee and capsule or from mechanoreceptors on ACL prevents to reach a certain decision about the mechanoreceptors of ACL [75].
Even after total knee arthroplasty, the contribution of the soft tissues around the knee to proprioception continues. In order to take advantage of this effect and ensure satisfactory outcomes in these patients, the soft tissue and gap must be well adjusted. Unicompartmental replacement protecting the ACL may be more advantageous in not reducing proprioception due to the proprioceptive effect of ACL. Also Ishii et al. [76] conclude that balance is improved after the postoperative period in bilateral total knee arthroplasty. It is stated that the first 6-week period is the critical period for adaptation time and proprioceptive loss after total knee replacement, and a new pattern in the knee load distribution occurs with postoperative rehabilitation [77].
4.2 Hip joint
Loss of proprioception, balance, sensation as joint position and kinesthetic are frequently observed in patients with knee osteoarthritis [78, 79]. Shakoor et al. [80] described significant sensory deficits associated with hip osteoarthritis, and these deficiencies involved both upper and lower limbs. The mechanism for this remains unclear; however, it has been suggested that there may be neurological feedback mechanisms or a inherent generalized neurological defect [78].
The greatest portion of mechanoreceptors and free nerve endings and highest concentration of pain receptors are located in the anterosuperior, posterosuperior and anterolateral labrum, respectively [81, 82].
There is no satisfactory information about proprioception impairment after surgeries due to hip pathologies. In the literature on the relationship between arthroplasty and proprioception, there are studies related to the knee rather than the hip. Interestingly, Ishii et al. [83] found no difference in proprioceptive responses among participants in the total hip arthroplasty, hemiarthroplasty and healthy control groups. They thought that the mechanoreceptors in the muscles, tendons and ligaments were responsible for joint proprioception rather than the intracapsular structures. While capsular receptors play a secondary role, muscle receptors play a primary role in hip proprioception. Therefore, it has been suggested that proprioception does not decrease after surgery, despite the capsule being removed during arthroplasty [84].
The effects of FAI and labral tear treatments on proprioception are not well known, but due to their proprioceptive properties, hip musculotendinous and capsuloligamentous tissues contribute to lower limb posture and stabilization through neuromuscular control. Therefore, preserving proprioceptive tissues as much as possible will prevent lower extremity injuries in arthroscopy operations.
4.3 Ankle joint
Ankle injuries are in the first place in sports-related injuries and lateral ankle sprains constitute the majority of this [85]. Unfortunately, many of these acute injuries can become chronic [86, 87]. Training, fatigue, and ankle injuries can affect ankle proprioception. Joint position sense, peroneal reaction time, EMG evaluation of peroneal muscles, and balance tests are tools to evaluate proprioception before and after ankle injuries or surgeries.
There are two important anatomical structures that provide proprioception and are located around the foot and ankle. Superior and inferior extensor retinaculum act as a pulley protecting tendons close to bony structures. The lateral ankle complex is the other anatomical structure with proprioceptive properties [88, 89]. Both acute and chronic injuries of the ankle can predispose the proprioceptors of the ankle. The differentiation in proprioception after these injuries were presented in the literature. While Vries et al. [90] stated that there was no difference between chronic ankle injury, acute trauma and healthy control groups, there are studies suggested that proprioception after acute inversion injuries and chronic ankle injuries are decreased [91, 92, 93]. Recovery of the proprioception is crucial after ankle injuries to maintain balance control. In order to achieve this, rehabilitation should not be neglected, especially after lateral ankle sprains.
A study conducted by Conti et al. [94] found no difference in proprioception between operated and non-operated side in total ankle arthroplasty. However, ankle arthroplasty has the worst outcome in terms of proprioception and balance compared to total hip and knee arthroplasty [95].
4.4 Shoulder joint
Some studies have revealed Pacinian corpuscles and Golgi tendon organ with mechanoreceptors in the shoulder [96, 97]. However, they discovered that while there are free nerve endings in the labrum and subacromial bursa, these structures do not contain mechanoreceptors. It is also thought that the supraspinatus muscle has more receptors than the infraspinatus muscle contains [98].
The pathological conditions of the shoulder joint can affect shoulder proprioception. Surgical shoulder diseases include rotator cuff tears, subcacromial pathologies, biceps tendon diseases and instabilities. Studies comparing pre- and post-surgical proprioception in the shoulder joint are not sufficient. In a study conducted by Aydın et al. [99], it was revealed that there was no difference in terms of proprioception between surgically treated and non-surgically treated shoulders in cases of instability. Duzgun et al. [100] stated a rapid recovery in shoulder joint proprioception after rotator cuff surgery as their experience.
Shoulder arthroplasty is thought to negatively affect proprioception. It has been stated that intervention to the subscapularis muscle and glenohumeral ligaments during shoulder arthroplasty may be effective in this decrease in proprioception [101, 102].
4.5 Elbow joint
Soft tissue damage is significant in elbow arthroplasty. Both flexor and extensor muscles are affected, collateral ligaments are released and capsule is removed. Therefore, the proprioceptive tissues as like skin, capsule, muscle and tendons are damaged. Despite the role of proprioception is still not well-established, one study was found an impairment in proprioception after total elbow arthroplasty [103].
In conclusion, proprioception may be adversely affected after joint surgeries. It should definitely be included in the rehabilitation program considering this situation. Proprioception seems to be an important factor for gaining balance and gait speed, especially after arthroplasties in the lower extremity.
Conflict of interest
The authors declare no conflict of interest.
\n',keywords:"proprioception, neurology, orthopedics",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/75009.pdf",chapterXML:"https://mts.intechopen.com/source/xml/75009.xml",downloadPdfUrl:"/chapter/pdf-download/75009",previewPdfUrl:"/chapter/pdf-preview/75009",totalDownloads:48,totalViews:0,totalCrossrefCites:0,dateSubmitted:"October 22nd 2020",dateReviewed:"January 7th 2021",datePrePublished:"February 5th 2021",datePublished:null,dateFinished:"February 1st 2021",readingETA:"0",abstract:"Proprioception is the sense of position or the motion of the limbs and body in the absence of vision. It is a complex system having both conscious and unconscious components involving peripheral and central pathways. The complexity of sensorimotor systems requires deep knowledge of anatomy and physiology to analyze and localize the symptoms and the signs of the patients. Joint sense and vibration sense examination is an important component of physical examination. This chapter consists anatomy, motor control, postural control related to proprioception with neurologic clinical correlation and also the information about the changes of proprioception after orthopedic surgeries and discuss with the available literature.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/75009",risUrl:"/chapter/ris/75009",signatures:"Pinar Gelener, Gözde İyigün and Ramadan Özmanevra",book:{id:"10554",title:"Proprioception",subtitle:null,fullTitle:"Proprioception",slug:null,publishedDate:null,bookSignature:"Prof. José A. Vega and Dr. Juan Cobo",coverURL:"https://cdn.intechopen.com/books/images_new/10554.jpg",licenceType:"CC BY 3.0",editedByType:null,editors:[{id:"59892",title:"Prof.",name:"José A.",middleName:null,surname:"Vega",slug:"jose-a.-vega",fullName:"José A. Vega"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:null,sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_1_2",title:"1.1 Anatomy",level:"2"},{id:"sec_2_2",title:"1.2 Proprioception and motor control",level:"2"},{id:"sec_3_2",title:"1.3 Proprioception and postural control",level:"2"},{id:"sec_5",title:"2. Clinical implications and evaluation of proprioception",level:"1"},{id:"sec_6",title:"3. Neurologic correlation",level:"1"},{id:"sec_7",title:"4. Proprioception after orthopedic surgeries",level:"1"},{id:"sec_7_2",title:"4.1 Knee joint",level:"2"},{id:"sec_8_2",title:"4.2 Hip joint",level:"2"},{id:"sec_9_2",title:"4.3 Ankle joint",level:"2"},{id:"sec_10_2",title:"4.4 Shoulder joint",level:"2"},{id:"sec_11_2",title:"4.5 Elbow joint",level:"2"},{id:"sec_16",title:"Conflict of interest",level:"1"}],chapterReferences:[{id:"B1",body:'Hillier S, Immink M, Thewlis D. Assessing proprioception: a systematic review of possibilities. Neurorehabilitation and neural repair. 2015;29(10):933-949. DOI:10.1177/1545968315573055'},{id:"B2",body:'Gilman S. 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DOI: 10.1007/BF01553524.'},{id:"B94",body:'Conti SF, Dazen D, Stewart G, Green A, Martin R, Kuxhaus L, et al. Proprioception after total ankle arthroplasty. Foot Ankle Int. 2008;29(11):1069-1073. DOI: 10.3113/FAI.2008.1069.'},{id:"B95",body:'Butler RJ, Thiele RAR, Barnes CL, Bolognesi MP, Queen RM. Unipedal balance is affected by lower extremity joint arthroplasty procedure 1 year following surgery. J Arthroplasty. 2015;30(2):286-289. DOI: 10.1016/j.arth.2014.08.031.'},{id:"B96",body:'Vangness CT Jr, Ennis M, Taylor JG, Atkinson R. Neural anatomy of the glenohumeral ligaments, labrum, and subacromial bursa. Arthroscopy. 1995;11(2):180-184. DOI: 10.1016/0749-8063(95)90064-0.'},{id:"B97",body:'Ide K, Shirai Y, Ito H, Ito H. Sensory nerve supply in the human subacromial bursa. J Shoulder Elb Surg. 1996;5:371-382. DOI: 10.1016/s1058-2746(96)80069-3.'},{id:"B98",body:'Windhorst U. Muscle proprioceptive feedback and spinal networks. Brain Res Bull. 2007;73:155-202. 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