**9. Conclusions**

In treating arterial ulcers it should be remembered that not all foot sectors share same ischemic affectation and that not all patients with comparable *macro*-vascular images bear same collateral reserve and related *micro*-vascular tissue recovery resources.

Contemporary research reveals astonishing multilevel anatomical and physiological intricacy of lower limb blood supply, viewed in a dynamic and time unfolding perspective. This apparent complexity represents but plausible challenges for the experienced interventionist availing high-performance macro and microcirculatory diagnostic and treatment methods for revascularization and tissue healing.


**1. Introduction**

336 Autoimmune Disorders – Current Concepts and Advances from Bedside to Mechanistic Insights

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Van den Hove, D.L., Steinbusch, H.W., Bruschettini, M., et al. (2006). Prenatal stress reduces

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Over the last decade, high-dose polyclonal intravenous immunoglobulin (IVIg) is used increasingly in the management of autoimmune conditions of the central and peripheral nervous system. Despite the expanded use of IVIg, the consensus on its optimal use is insufficient. Currently chronic idiopathic demyelinating polyneuropathy (CIDP), Guillain – Barre syndrome (GBS) and multifocal motor neuropathy (MMN) are the three major immune neuropathies, in which the latest evidence strongly supports the use of IVIg as a first-line therapy. In addition to these disorders, there is a rising number of other neurological indications in which IVIg has been used as a therapy, even though the available evidence-based data are relatively sparse and less convincing. Due to increasing costs of this treatment and relative shortage of products, careful selection of patients who will benefit from IVIg is extremely important (Elovaara & Hietaharju, 2010).

In this paper the current literature on the use of IVIG in treatment of neurological diseases has been reviewed and evidence-based recommendations, as well as less convincing data and future possibilities for its use in these disorders are presented.


*3.2. Path Planning Algorithms Considering Depth Hazard*

According to the results of the hydrodynamic analysis in Section 3.1, the minimum water depth required for safe navigation of unmanned surface vehicles is calculated by Equation (11):

$$S\_{\rm min} = z\_{\rm max} + 0.5L \tan \theta\_{\rm max} + T + e\_{\rm env} \tag{11}$$

where, *z*max is the largest downward settlement of the USV in several irregular waves at different speeds, *L* is the length of USV, θmax is the maximum trim angle, *T* is the average draft of the USV, and *eenc* is the depth error of ENC are considered. According to the minimum safe water depth for an unmanned surface vehicle, the restricted sea area of the unmanned surface vehicle is calculated, and the obstacle region is updated. The cost of water depth hazard in the obstacle region is set to 1.

Define the depth hazard of nodes *Ni* in feasible space as follows:

$$r(N\_i) = \frac{S\_{\min}}{D(N\_i)}, (0 < r(N\_i) < 1), \tag{12}$$

*D*(*Ni*) is the average water depth of each grid calculated by the interpolation algorithm in Section 2.2.

Total depth hazard of planned path is calculated by Formula (13):

$$\mathcal{R}\_{\mathbb{S}} = \sum\_{i=1}^{N} r(\mathcal{N}\_{i})\_{\prime} \tag{13}$$

where, *i* is the index of the grid through which the path passes, and *N* is the total number of all the grids through which the path passes. The depth hazard distribution map calculated by the combination of depth area and Formulas (11)–(13) is shown in Figure 9. The depth hazard map will be used as the input map of the path search algorithm.

**Figure 9.** The depth hazard distribution map.

The depth risk map and A\* algorithm are applied to plan the path. A\* algorithm was proposed originally by Hart Peter et al. [9]. The algorithm searches the minimum cost path from the starting node to the terminating node through the minimum cost function (15),

$$h(N\_i) = \sqrt{(\mathbf{x}\_{N\_i} - \mathbf{x}\_G)^2 + (y\_{N\_i} - y\_G)^2},\tag{14}$$

$$f(N\_i) = g(N\_i) + h(N\_i),\tag{15}$$

where *g*(*Ni*) is the actual distance cost from the ith node *Ni* to the starting node S that has been paid in the raster map namely the distance traveling from the start node S to the *i*th node *Ni*. *h*(*Ni*) is the heuristic distance from the start node to the goal node which has a great influence on the performance of A\* algorithm, in which (*xNi* , *yNi* ) is the coordinate the center of node *Ni* and (*xG*, *yG*) is the coordinate the center of goal node G. If it is always lower than (or equal to) real value, the shortest path can be found. The lower the number of extended nodes is, the slower the search speed. If it is equal to the actual value, the search only follows the best path and does not expand the redundant nodes, so the search speed is the fastest. If it is larger than the actual value, the shortest path cannot be guaranteed, but the search path is faster. In this paper, the Euclidean distance is chosen as a heuristic value when calculating the shortest distance path. Euclidean distance can ensure that the solution can be found if there is a shorter path. The shortest path planned by A\* algorithm combined with the grid method is presented in Figure 10b.

**Figure 10.** A\* path planning algorithm schematic diagram. (**a**) Schematic of adjacent node expansion; (**b**) The shortest path of A\* algorithm. The green star represents the starting point, and the yellow diamond represents the goal point. The shortest path is the black line between the starting point and the end point. The color grids are expanded nodes. The deeper the blue is, the closer the starting point is, and the deeper the red is, the closer the end point is. A set of white grids represents a feasible space, and black grids are obstacles.

The heuristic function of A\* algorithm considering depth hazard degree is defined as:

$$f(N\_i) = g(N\_i) + h(N\_i) + a \sum\_{i=1}^{N\_c} r(N\_i) \tag{16}$$

Not only the distance cost should be considered, but also the depth hazard, and the nodes with lower depth hazard degree should be selected to expand in neighbor nodes when expanding nodes. In Formula (14), *g*(*Ni*). The distance cost from the *Ni* node to the starting point S. *h*(*Ni*) is the heuristic distance cost from the *Ni* node to the goal node, *N c i*=1 *r*(*Ni*) is the water depth hazard cost sum from the starting node to the current node, and α is the constant greater than 0 used to control the weight of the risk cost in the total cost, thus controlling the impact of the water depth hazard on the final path. The pseudo code chart of the water depth risk level A\*(WDRLA\*) algorithm considering depth hazard is shown in Figure 11.

**Figure 11.** WDRLA\* algorithm pseudo code chart.

## **4. Discussions**

The spline function interpolation method with obstacles is performed to get the raster depth area with the water depth point selected as input point feature and the smoothing coefficient chosen as 0 and the grid size set as 25 m. The feasible space is updated according to the calculated minimum depth of safe navigation (1.29 m). Related parameters are shown in Table 6. The simulation is also based on the following assumptions: Assuming the unmanned vehicle as a mass point, unmanned vehicles can safely cross the junction vertex of the blocked grid and free gird between the obstacle area and the non-obstacle area, and unmanned vehicles can complete the turnaround operation in the grid. The proposed approach is simulated using Matlab R2018b. All simulations are performed on a PC with Microsoft Windows 10 as OS with Intel i5 2.712 GHz quad core CPU and 8 GB RAM.

**Table 6.** Table of Related parameters.

The positions of USV are represented by the grid index value of row and column where the point is located. S(500, 500) is chosen as the starting node and G(650, 650) as the goal node. Three kinds of cost function, including only distance, cost seeing Equation (15), only risk level cost seeing Equation (13), cost of combining seeing equation (16), were used to calculate the paths of shortest distance path (SDP), the shorter and safer path (SSP), the safest path (SFP) The results are shown in Figure 12. Compared with Figure 12a–c, it can be seen that the path planning algorithm considering water depth risk level will lead to more expanded nodes, so the search speed will be slower than A\* and the expanded nodes of WDRLA\* is less than those of SFP seeing Figure 12b,c. Figure 12d,e indicate that there is little difference between SSP and SFP, which means approximate depth risk level, but SDP is closer to the obstacle, so the risk level is much higher. Water depth risk level A\* algorithm (WDRLA\*) can reduce the depth risk and improve the safety of path, but sacrificing a certain calculation time.

**Figure 12.** Comparison of three kinds path. (**a**) Shortest distance path (SDP) that ignores the depth risk; (**b**) Shorter and safer path (SSP) that considers the depth risk level and distance. (**c**) Safest path (SFP) that considers only the depth risk. The colorful grids in figure (**a**–**c**) are extended nodes. The space of white grids represents the feasible space, and the black grids are obstacles. (**d**) Three paths, shown on the depth distribution map. (**e**) Three paths, shown on the depth risk level distribution map. (**f**) Three paths, shown on S57 ENC. The black line is the SDP, the blue one is SSP, and the purple one is SFP.

Take S(710, 902) as the starting node, and G(990, 1408) as the goal node, Results of three kinds of paths are shown in Figure 13. From Figure 13, it can be drawn that there are marked differences between SDP and SSP in shallow coastal waters. SDP passes through a narrow channel with shallow water depth which is more dangerous, while SSP and SFP avoid narrow channel by choosing deeper water area, where SSP reduces the risk of the path by 39.61% (see Table 7). At the same time, the number of extended nodes increases greatly, so WDLRA\* path search process is slower than A\*. SSP increases 1652m and 10.54% in length compared with SDP. The length of SSP and SFP is approximate, but SSP with less expanded nodes.

**Figure 13.** Comparison of three kinds path. (**a**) SDP that ignores the depth risk; (**b**) SSP that considers the depth risk level and distance. (**c**) SFP that considers only the depth risk. The colorful grids in figure (**a**–**c**) are extended nodes. The space of white grids represents the feasible space, and the black grids are obstacles. (**d**) Three paths, shown on the depth distribution map. (**e**) Three paths, shown on the depth risk level distribution map. (**f**) Three paths, shown on S57 ENC. The black line is the SDP, the blue one is SSP, and the purple one is SFP.

**Table 7.** Comparison of different starting and goal points.

In order to determine the reliability and consistency of the algorithm furtherly, disparate starting nodes and end nodes cases are simulated, and several parameters, such as the path length, the number of expanded nodes, and the risk level of the path, are compared simultaneously, in which the depth risk level is calculated by Equations (11)–(13). All of the results are shown in Table 7. From Table 7 combined with Figures 12–14, it can be seen that the depth risk level of the path can be reduced, and the path is relatively short, especially in the area with complicated underwater topography, such as Figure 13 with WDLRA\* algorithm, but in the cost of decreasing computational efficiency with redundant expanded nodes (see Figures 12c and 13c). This method can ensure the safety of small USV navigating in complicated sea areas.

**Figure 14.** The comparation of key parameters of three different sorts of paths. (**a**) The total distance of the path. The unit of distance is m. (**b**) Water depth risk level of the path. (**c**) The number of expanded nodes of three sorts of cost functions.


**3. Scour around Bridge Foundations**

Comprehensive studies on the variables controlling the maximum scour depth have been conducted since the state-of-the-art paper by [28]. The available information mostly corresponds to the case of scour in sand, with few exceptions for cases of scour in fine sediments [29–32] and gravel bed rivers [33–38]). Further, researchers have concentrated on the dynamics of scour [39–42]. A detailed description of the functional relationships between scour and its controlling variables [43,44] are out of the scope of the present paper. In this section, we focus on scour patterns.


**2.4 Persistence of pain**

The overall emerging theme reported by participants was the persistence of pain as a result of their scoliosis. This replicates earlier work that has found that for patients who have a form of degenerative scoliosis, lower back pain is the most common presenting symptom [19, 20]. Further work has found that older adults with degeneration believe they are in more pain than both younger adults and adults with standard lower back pain [7, 15]. This research study has highlighted the severity of pain that older people with degenerative scoliosis experience. When the researcher asked the participants questions about their pain and how much pain they were in, they reported a number of difficulties in carrying out everyday activities as a result of the severity of their pain as seen below:

*Some days I cannot move the pain is that bad, it takes me over 40 minutes to do my hair.  (Patient 3)*

Further analysis indicated that the pain the participants were living with had substantial limiting effects on both their activity levels and the activities that they could participate in; these activities were virtually limited to home-based stationary activities such as watching TV. Furthermore, household tasks were also limited to very basic chores such as folding, washing or drying dishes:

*No nothing, I can do nothing (P8)*

*A Mixed Methods Study of the Experiences and Effectiveness of a Soft Brace for Adults… DOI: http://dx.doi.org/10.5772/intechopen.92387*

*I cannot clean the floor and I cannot even stand to do my ironing (P6)*

Participants also identified problems with sleeping before they received the brace, stating that the constant pain they experienced due to their scoliosis significantly disrupted their sleeping patterns.

*I could not move, and I could not be touched, even the bed covers could not be on me (P4)*

*I did not sleep very well at all, because if I moved anywhere, I was, I was erm, I was woken up by the pain, I could not get really comfortable, the pain also had a huge impact on my social life, I ended up with no social life at all, people use to come and see me for a while, but you know, over a year that drops off (P5)*

Other individuals also echoed that before receiving the brace, their activity levels were minimal as a result of their scoliosis.

*I could not walk very far at all. It's affected my life a lot as I used to be dancing all the time, and now I cannot even stand up for a while let alone dance (P6)*

*It's cut off my social life a lot as I cannot play badminton like I used to (P4)*

In essence, pain was a central theme of the patients' experiences of living with scoliosis: all participants explained that they were in constant pain as a result of their scoliosis. From the responses the participants made in relation to living with scoliosis, it was apparent that pain had a substantial effect on all aspects of their lives and on a daily basis. Upon further analysis, a sub-theme emerged which focused on how the pain limited participation in activities, with some reporting only being able to carry out essential household tasks (P6), to the basic challenges of sleeping (P5). Furthermore, the participants' answers to the questions also gave the researcher a base for comparison before they started the trial and once they received the brace.

### **2.5 The impact of the brace on pain and daily living**

The next theme that emerged from the researcher's questions indicated that the patients experienced a small reduction in pain whilst wearing the brace, which in turn led to a positive impact on their activity levels. When the participants were asked if the brace had allowed them to be able to participate in any additional activities or participate longer in activities they could already do, the participants gave answers such as:

*Well I can walk further with my walkie frame (P1)*

*If anything, it's helped me going up and down the stairs as it keeps me more upright, I used to go up and down stairs on my hands and knees but the brace keeps me more upright instead of crawling (P4)*

Further quotes revealed the brace reduced the level of pain that participants reported whilst walking or carrying out everyday tasks.

*My pain has improved yes, especially when I'm sleeping or doing household chores (P5).*

*Yea, it helps, it really helps, it helps to get me out, it gets me moving. (P6)*

*I have got totally active again since receiving it. (P4)*

However, it emerged a reduction in pain was not the belief or views of all the participants, as other participants did not believe they received any benefits from the brace, to the extent that one participant even believed wearing the brace was leading to an increase in their pain.

*Yea my back has started to get worse. (P7)*

*It's affected my sleeping; my sleeping has got worse it feels as if it pulls me into painful positions. (P8)*

In summary, the participants generally indicated that the brace was having a positive impact in terms of improving their quality of life and their overall activity levels. With regard to participants 7 and 8, both dropped out of the trial shortly after this interview.

### **2.6 Problems with the brace**

Patients reported several design problems with the brace that limited the amount of time the participants were able or willing to wear the brace. This was particularly problematic as previous research has shown that bracing is only effective when worn for the recommended time (Rowe et al. and Maruyama et al.) [21, 22]. Participants indicated that they were not adhering to the 8 hours a day, 7 days a week, minimum recommended wearing time that was required to achieve maximum efficiency. They gave a number of reasons for this. When asked how long they were wearing the brace, the participants answered:

*Well approximately 4 days a week, but it really depends on what I'm doing. (P6)*

*I wear it when I'm in the house, but I cannot wear it whilst I'm out as I cannot get it off. (P2)*

Further probing revealed the main reason the participants were not keeping to the recommended wearing time was the brace's practicality and functionality with regard to using the toilet, due to the design of the shorts.

*I find it's really difficult to take it off so I do not when I'm going out. (P2)*

*Because I find the use of the toilet very difficult if we are going to the theatre or places like that. (P5)*

*It's a bit awkward to get it off, if you were to need the toilet. (P6) The only problem is going to the toilet. (P3)*

Furthermore, additional problem participants identified, as a reason for not fulfilling the recommended wearing time, was the cosmetic appearance of the brace under their clothes.

*A Mixed Methods Study of the Experiences and Effectiveness of a Soft Brace for Adults… DOI: http://dx.doi.org/10.5772/intechopen.92387*

*You know, I cannot wear my clothes properly because of that bump in my shoulder from the shoulder strap, in fact it's not the strap, it's the back of the jacket thing that comes across the back of my neck, well it always shows, no matter what I wear. (P4)*

In summary, participants reported several design issues with the brace, which limited the amount of time they could wear the brace for. As a result of these problems, the optimum recommended wearing time was not achieved, which would have reduced any benefit of the brace. The main reason reported for this noncompliance wearing the brace was toileting as a result of the design of the brace shorts, a problem that was exacerbated by the fact that several participants could not remove or fit the brace independently.

### **2.7 Trial satisfaction**

From the final set of questions, the theme that emerged was that participants were happy with the format of the brace trial. This was in regard to the frequency and duration of the clinical visits and the questionnaires the participants had received.

*No, I think they the questionnaires ask the right thing really, they are simple to answer, I have not found them simple to answer as I've been in a lot of pain last month with my IBS but normally, I'm ok with them. (P4) The questionnaires are simple really; they ask sensible questions and the number of visits is fine also. (P2)*

The answers from the remaining participants who reached the 6-month treatment point also indicated they were happy to continue with the trial. Participants gave generally brief responses to these questions; they did not expand or give any extra information to the questions asked. Participants indicated they were happy with the format of the trial and felt the questionnaires were appropriate; they also indicated they were happy to continue with the trial.

### **2.8 Interviews with the participants who had withdrawn from the trial**

The interviews with the participants who had dropped out of the trial were carried out over the telephone and recorded with their permission; consent forms were sent out in the post prior to the interview. The interview schedule followed the same progression as the treatment group, with the initial questions focused on the participants' life before they received the brace. The participants indicated the primary complaint of living with scoliosis was their persistent pain.

*Erm, very bad, well to my mind it was very bad, but I'm sure there must be people who are worse. (P7)*

*Yes, yes I cannot, I can no longer go shopping for example, Christmas shopping for example is an absolute nightmare really, erm, you know the weekly shop, my husband has to do it now, the only time that I'm alright is if I'm pushing the trolley, it's almost like I can run then. (P8)*

The next set of question focused on why the participants dropped out of the trial. Participants provided answers identifying the primary reasons being the fitting of the brace.

*I could not wear it because I take diuretic tablets and I could not get the brace off and I kept needing to go to the loo all of the time. If something like that could be devised and designed with erm, with easier fittings because I need to have somebody to help me get in and out and quite often, they could not understand it either. (P7)*

Furthermore, one participant indicated the reason they dropped out of the trial was due to the bracing causing them even more pain.

*I did not wear the brace for any length of time because it hurt my body, that might sound silly but it actually hurt; it hurt my stomach for example, it just seemed altogether too tight and pulling me, although when it was on for a short length of time it was quite good. (P8)*

In summary, it was apparent the design of the brace and its practicalities were the main factors for these participants dropping out. Furthermore, the brace also led one participant to believe their pain increased; however, as stated earlier in this study, this participant was only included due to the small study numbers and at the specific request of the consultants.

### **2.9 Discussion**

The primary aim of this study was to use a qualitative approach to explore the patients' experiences of living with scoliosis. Furthermore, the secondary aims of the study were to obtain rich and in-depth qualitative information with regard to how the brace affected the scoliosis, together with the functionality and practicalities of the brace design. The results and themes generated from the semi-structured interviews indicated that the primary experience of living with scoliosis is one of persistent pain and limited activity, with all participants who were interviewed identifying these two factors as the main issues. Furthermore, the results from the interviews also identified and highlighted design problems and limitations with the brace shorts that were previously unknown. As the brace has previously only been used on adolescents [9, 23, 24], the problems experienced by adults with regard to the design of the shorts were previously unknown. It is unclear why older women had a problem with the design when this issue has not to our knowledge been reported elsewhere.

An additional result from this study was the identification that the literature on adults' experience of living with scoliosis is very sparse. The data obtained from this study contributes significantly to the gap in knowledge with regard to the experiences of living with scoliosis and its effectiveness. From the responses participants gave, the brace did offer a reduction in the participants' reported pain and allowed them to take part in a wider range of activities. However, for a more definitive conclusion and indication as to how successful the brace has the potential to be, this study would need to be carried out on a larger sample size. Furthermore, the participants would need to be willing and able to wear the brace for the recommended time and would need to fully match the study criteria.

Furthermore, as the interviews provided a greater reflection of the experiences of living with scoliosis, it is suggested that each participant should receive a minimum of three interviews in any future trial. The first interview would be scheduled at the beginning of the trial, one in the middle and one at the end of the study. The implementation of three interviews would also allow for a more in-depth comparison to be obtained, as the interviews would be more frequent and the participants would be able to give more detailed descriptions of their experiences of living with the brace.

*A Mixed Methods Study of the Experiences and Effectiveness of a Soft Brace for Adults… DOI: http://dx.doi.org/10.5772/intechopen.92387*

The information obtained from the qualitative interviews allowed for a greater understanding of patients' experiences of living with scoliosis that the questionnaires failed to capture, such as problems with the brace and the extent to which the brace was helping with their pain and activity levels. Furthermore, Participant 4's answer to the set of questions regarding trial satisfaction also showed how some patients found it difficult to that they experienced was due to IBS or scoliosis. This qualitative study also revealed that patients' experiences of pain had a limited effect on the amount of activity they could do due to their degenerative scoliosis.


Preface

Pharmacoepidemiology is a relevant emerging field that applies epidemiological methodologies to study the interactions between health products and large human populations in real-life settings, namely the effects, benefits, and risks of drug use, with the goal of endorsing/optimizing their rational use to improve health outcomes. Pharmacovigilance, or drug safety, is a significant area within pharmacoepidemiology, and addresses the assessment, detection, monitoring, and prevention of adverse drug reactions, thus being fundamental for recognizing the safety of medicines and, at the same time, preventing patients from potential harms.

*New Insights into the Future of Pharmacoepidemiology and Drug Safety* provides scientific information on important subjects within the fields of pharmacoepidemiology, pharmacovigilance, and drug safety, aiming to improve public health surveillance and shed light on some critical unexplored concepts. Furthermore, it allows readers to acquire an in-depth understanding of the main roles, key principles, developments, and practices adopted in these disciplines while also highlighting their latest advances. This book is for students and those working in pharmacology, epidemiology, drug safety, clinical research, regulatory affairs, pharmacovigilance, and risk management, including researchers, health professionals, and employees from clinical research organizations.

The book contains ten chapters divided into four sections. The introductory chapter "Pharmacovigilance and Public Health Safety" offers a comprehensive overview of the key features of pharmacovigilance and its high importance in preserving public health by enhancing patient safety and quality of life. The remaining nine chapters are included in the following sections.

Section 2, "Recent Findings and New Advances of Adverse Drug Reactions," includes the following five chapters: "Adverse Drug Reactions and Pharmacovigilance," "Adverse Drug Reactions Associated with Anti-Tuberculosis Therapy," "Prevalence and Significance of Antibiotic-Associated Adverse Reactions," "Evaluation of the Medication Safety of Chemotherapy Drugs," and "Small Molecule/HLA Complexes Alter the Cellular Proteomic Content." These chapters explore the significant benefits of monitoring and reporting adverse drug reactions while a drug is in clinical trials as well as after its market authorization. Drugs examined include those used for anti-tuberculosis therapy and chemotherapy as well as antibiotics. Furthermore, this section also reviews the epidemiological data related to antibiotic-associated adverse reactions and analyzes drug–protein interactions within the human leukocyte antigen (HLA) system and its association with adverse drug reactions and disease.

Section 3, "Drug Safety among Older People," includes the two chapters: "Pharmacovigilance in Older Adults" and "Drug-Induced Delirium among Older People." These chapters study the interactions between polypharmacy and adverse drug effects in older adults, such as delirium, namely through the prescription of inappropriate medication, thus highlighting the importance of encouraging pharmacovigilance practices among this special population.

Section 4, "Scientific Methods and Tools for Safety Surveillance" includes two chapters: "Computer-Aided Pharmacoepidemiology in Drug Use and Safety: Examining the Intersection between Data Science and Medicines Research" and "Basics and Essentials of Medical Devices Safety Surveillance." These chapters explore the increasing use of real-world data in pharmacoepidemiologic research and medication safety, while at the same time assessing the main strengths and limitations of relevant healthcare tools such as electronic databases and medical devices.

In sum, this book provides a general overview of past and new scientific research developments in pharmacoepidemiology and drug safety, as well as reinforces the main goals, strengths, and limitations of the most critical concepts within these fields.

#### **Maria Teresa Herdeiro and Tânia Magalhães Silva**

iBiMED – Institute of Biomedicine, Department of Medical Sciences, University of Aveiro, Aveiro, Portugal

#### **Fátima Roque**

Research Unit for Inland Development – Guarda Polytechnic Institute (UDI-IPG), Guarda, Portugal

> Health Sciences Research Centre, University of Beira Interior (CICS-UBI), Covilhã, Portugal

#### **Adolfo Figueiras**

Health Research Institute of Santiago de Compostela (IDIS), University of Santiago de Compostela, Santiago de Compostela, Spain

Consortium for Biomedical Research in Epidemiology and Public Health (CIBER Epidemiology and Public Health - CIBERESP), Madrid, Spain

Section 1 Introduction

#### **Chapter 1**

## Introductory Chapter: Pharmacovigilance and Public Health Safety

*Maria Teresa Herdeiro, Tânia Magalhães Silva, Inês Ribeiro-Vaz, Eva Rebelo Gomes, Adolfo Figueiras and Fátima Roque*

#### **1. Introduction to pharmacovigilance**

Worldwide, pharmacovigilance is one of the most important scientific disciplines within public health [1]. According to the World Health Organization (WHO), pharmacovigilance is described as "the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug-related problem" [2]. The implementation of pharmacovigilance activities was essential to globally promote and protect public health, particularly by reducing the significant burden of morbidity, mortality and associated increased healthcare costs, triggered by the occurrence of adverse reactions to medicines [3]. The Memo/08/782, released in 2008 by the European Commission, highlights the importance of pharmacovigilance, namely for saving lives, by revealing estimates of about 197 thousand deaths per year and total costs to society of 79 billion euros in the European Union (EU), due to adverse reactions [4].

The fundamental goals of pharmacovigilance are [5–7]:

In sum, the golden objective of pharmacovigilance process is to enhance patient's safety and quality of life, and strictly preserve public health by identifying, preventing or decreasing the harmful effects and risks related to the use of health products in humans. Therefore, the science that assesses drug's safety and efficacy profiles stands as highly important throughout the entire drug development lifecycle, from preclinical development until post-market surveillance, as it promotes the continuous vigilance of the drug effects. It plays a crucial role within pharmaceuticals, not only for the prevention of drug-related risks in humans, as well as for the reduction of the financial expenses linked to the occurrence of unexpected adverse effects [5–8].

#### **2. Pharmacovigilance history**

Pharmacovigilance has a long history. Although the first findings were dated from 172 years ago, when a patient died after being anesthetized with chloroform, followed by 107 deaths in the United States of America in 1937, due to the high toxicity caused by diethyleneglycol, a sulfanilamide elixir-containing solvent, its official inception to address drug safety problems was only heralded after the thalidomide tragedy, in 1961 [1, 8]. This drug was commonly used in Europe by pregnant women as a nonaddictive, nonbarbiturate sedative for nausea treatment, and resulted into a devasting 10 thousand birth abnormalities, namely phocomelia, and increased miscarriage rates [9]. At that time, Dr. McBride highlighted the link between the consumption of thalidomide in pregnancy and the prevalence of fetal congenital malformations, by writing a letter to The Lancet journal editor and reporting an increase of 20% in these cases. In response to the thalidomide disaster, it became evident the urgency in requiring the rigorous safety and efficacy testing of drugs before their market authorization, as well as a global awareness concerning the need for creating pharmacovigilance systems [8].

The pharmacovigilance system suffered many alterations since then and, due to a collaborative effort of many stakeholders, such as physicians, pharmacists, other healthcare professionals, patients, regulatory health authorities, academia and industry, in 1968 the WHO Pilot Research Programme for International Drug Monitoring was instituted. This program intended to establish an active, systematic, organized and regulated network at an international level, mainly for uncovering formerly unknown or poorly recognized drug's adverse effects, leading to the formal adoption of the pharmacovigilance term in the 1970s [7, 8]. In early 1980s, the Council for International Organizations of Medical Sciences (CIOMS) introduced its programme on drug development and usage, together with WHO. In the 1990s, a remarkable impact on international drug regulatory activity was observed, specifically after the implementation of various of the recommendations provided by CIOMS by the formerly International Conference on Harmonization (ICH), currently known as International Council for Harmonization [1, 7, 8]. The ICH helped to harmonize the regulatory infrastructures of the regulatory agencies and pharmaceutical companies from Europe, Japan and the United States [1]. Thereafter, a positive development was observed in several countries, concerning the organization and associated regulations of drug safety, ultimately resulting in the creation of the European Society of Pharmacovigilance (ESOP) in 1992, posteriorly renamed to International Society of Pharmacovigilance (ISoP). Finally, in 1995 the European Medicines Agency (EMA) was founded, followed by the Eudravigilance launch in 2001 [7, 8].

Besides thalidomide disaster, another significant landmark in the history of pharmacovigilance was the market authorization of rofecoxib, a cyclooxigenase-2 *Introductory Chapter: Pharmacovigilance and Public Health Safety DOI: http://dx.doi.org/10.5772/intechopen.95293*

inhibitor. In the end of 2000, the Vioxx Gastrointestinal Outcomes Research (VIGOR) study revealed an association between rofecoxib consumption and myocardial infections in patients with chronic pain [10–12]. By this time, this risk became a critical public health issue as rofecoxib was prescribed to tens of millions of people in more than 80 countries. This was one of the most highly publicized drug withdrawals ever reported and, together with other subsequent related episodes, raised some concerns regarding public trust on the role of pre- and postmarketing surveillance [10–13]. Due to the public's lack of confidence on pharmacovigilance, more robust regulations had to be adopted [12, 14]. These include, for instance, the EU risk management plan, implemented in 2005, which became a mandatory document for marketing authorization applications to evaluate the information on drug toxicology, the request for a pharmacovigilance plan as well as for epidemiological information on the population receiving the drug therapy, and the submission of protocols to the regulatory authorities prior to the study start for a proper safety assessment [12]. Other important measures implemented were the education of physicians and medical students, active participation of other health professionals (pharmacists, nurses) in adverse drug reaction (ADR) reporting, feedback transmission and improvements on ADR reporting [14]. The introduction of all these approaches were essential to safeguard public health, with the particularity of primarily assessing the effects on the population, especially on the patient, rather than over the drug under study [6, 12].

#### **3. Pharmacovigilance systems**

Given the high importance of pharmacovigilance, currently, countless countries around the world already have well-established, active and robust national pharmacovigilance systems to safeguard patient's wellbeing.

Pharmacovigilance activities of these systems can also involve the [1]:

Therefore, it is not surprising that the WHO programme, responsible to aid in the design, development and assistance of the pharmacovigilance systems, has already 170 countries as partnership members [15].

#### **3.1 WHO collaborating Center for International Drug Monitoring: the Uppsala monitoring Center**

As previously referred, the WHO Programme for International Drug Monitoring started, in 1968, to systematically collect all available information on drug's adverse effects, as a worldwide response to the thalidomide disaster. Ten years later, in 1978, with the intuit to support this programme, the Uppsala Monitoring Center (UMC) was set up. The UMC is an international, independent and non-profit center in

Uppsala, Sweden, devoted to investigating the harms and benefits of medicines, to ensure a safe and efficient consumption of these drugs by patients [5, 7].

The key mission of UCM, on behalf of the WHO, is to protect patients through an effective and global pharmacovigilance practice, namely the management of the international database of ADR reports received from each country national center, within the WHO's global pharmacovigilance network [5, 7]. This distinctive WHO data repository, known as VigiBase, is the world's single largest database system of individual case safety reports (ICSR), which are solely submitted by members of the WHO programme [16]. The ICSR, also commonly recognized as "spontaneous" or voluntary ADR report, is a safety document that includes the information needed to support the reporting of adverse events, as well as of products-related problems and consumer complaints generated during the drug post-marketing phase. An ICSR can be filled either in paper or electronically and, to be considered as valid, has to include at least the following four elements: an identifiable patient, one identifiable reporter, one suspected medicinal product and one suspected adverse event [17, 18].

In sum, firstly the national pharmacovigilance system of each country receives the spontaneous ADR reports from health professionals, consumers and pharmaceutical companies. Afterwards, the ICSR are locally validated and evaluated, and a regulatory action can be potentially initiated, if needed. Finally, all the member countries are committed to disclose the on-time reports comprising complete postmarketing data into VigiBase, therefore enabling the uncovering of ADR-associated signs between different countries.

Until May 2019, VigiBase has held over 20 million of ICSR associated with medicines [16]. VigiBase collects the reports sent by the member countries of the WHO program, including 140 full member countries and 30 associate members [19]. The majority of the national joining centers have a straightforward electronic access to these standardized and structured reports, which contain a specific hierarchical code for the particular ADR registered, aiming to help in the fast identification of signals by any country member [5, 7]. The terminologies established for coding adverse reaction terms within the WHO programme, such as the WHO – Adverse Reaction Terminology (WHO-ART), afterwards replaced by the Medical Dictionary for Regulatory Activities (MedDRA), have been broadly embraced by national centers, manufacturers and medicinal product regulators [5, 7].

Spontaneous reporting systems are indispensable to post-marketing surveillance, and have shown to be effective in detecting various types of ADR, especially rare ones. Moreover, the ADR report method also evaluates the need to pursuit further investigations to check if exists an association with the medicine and can hence trigger alarm signals [20]. However, the search for complements to the existing pharmacovigilance systems has shown to be extremely important, mainly due to the significant delays encountered on the detection of more common types of ADR, in addition to the persisting high amount of unreported ADR [20].

#### **3.2 European Medicines Agency**

Globally, it is possible to find a selection of regulatory authorities whose main function is to regulate and support pharmacovigilance. For instance, while in the United States, the responsible structure is the Food and Drug Administration (FDA), in the EU is the EMA [21].

Briefly, EMA's gold mission relies on the promotion of scientific merit pertaining to medicine's evaluation and oversight, for the benefit of public and animal health in the EU. In compliance with the EU legislation requirements, EMA's main responsibilities are related to the:

The legal pharmacovigilance framework for human medicines marketed within the EU/European Economic Area (EEA) is given in Regulation (EC) No 726/2004, with regard to the EU authorized medicinal products, and Directive 2001/83/ EC, concerning the nationally authorized medicinal products, together with the Commission Implementing Regulation (EU) No 520/2012, which summarizes the practical aspects and obligations to be respected and followed by marketing authorization holders and regulatory authorities. Posteriorly, the Directive 2010/84/EC was introduced to substitute the previous directive, with minor amendments being performed in 2012. The EU law requires marketing authorization holders, national competent authorities and EMA to operate services and processes in line with EU legislation, aiming to support a quality assured EU regulatory pharmacovigilance system and to reduce the number of ADR in EU [21–23]. The EU pharmacovigilance system is one of the most sophisticated and comprehensive in the world and allows monitoring the safety of medicines on the European market through prevention, detection and assessment of adverse reactions to drugs, leading to an increased level of public health protection throughout the EU. This system operates through a robust and close collaboration between the competent regulatory authorities from the EU member states, EMA (system coordinator responsible for centrally authorized drugs) and the European Commission (competent authority for drugs centrally authorized in the EU), to rapidly manage and act against an emerging problem, unceasingly prioritizing a safer and more efficacious access of patients to medicinal products. The Pharmacovigilance Risk Assessment Committee (PRAC) was formed in response to this need in July 2012, thus being responsible to provide recommendations on all aspects related to human drugs risk management [21–23].

The European pharmacovigilance network not only successfully collaborates at the European level with high transparency, but also coordinates the necessary regulatory actions, hence producing efficient and accurate safety results able to be transmitted to the EU public in a timely manner. Some of the regulatory tools accessible after the implementation of the revised legislation involve risk management planning, signal detection and management at EU level, periodic safety update reports assessment, drug reviews through referrals post-authorization safety and efficacy studies, communication and training [23].

Within EU, the implementation of the different national pharmacovigilance systems occurred at distinct times. In 1963, The Netherlands became the first EU country to launch their own pharmacovigilance system for spontaneous ADR reporting, followed by the United Kingdom, in 1964, via the Yellow Card Scheme [24].

To achieve a consistent pharmacovigilance system, it is imperative that guidelines and standards are established as they clarify the practical details of the intended information flow, thus being very valuable, for instance, for health professionals training [5]. Thereby, the pharmacovigilance legislation in force in EU since

#### *New Insights into the Future of Pharmacoepidemiology and Drug Safety*

July 2012 led to the development of an important set of principles and measures on Good Pharmacovigilance Practices (GVP), to conduct the safety monitoring of medicines in EU [25]. One of the EMA's advisors on the development of these guidelines and standards on operational features of the EU pharmacovigilance is PRAC [22]. The GVP guidelines, covering medicinal products authorized in the EU either centrally via EMA or nationally, apply to EU marketing authorization holders, EMA and the competent authorities from each member state. The GVP can slightly differ between countries, thus being established by each country regulatory authorities. Moreover, the guidelines set is divided into two chapter types [25]:

Although EMA is known to support several pharmacovigilance databases, the network system used for collecting, managing and analyzing suspected ADR related to authorized medicines within EEA is EudraVigilance. This electronic reporting database system allows the early detection of potential safety signals of post-marketed drugs by effectively analyzing the spontaneous reports previously submitted by marketing authorization holders and member states [26].

The **Figure 1** below synthesizes the key features of pharmacovigilance for the global protection of the public health.

**Figure 1.**

*Pharmacovigilance (PV) highlights in public health safety.*

#### **Appendices and nomenclature**

*Introductory Chapter: Pharmacovigilance and Public Health Safety DOI: http://dx.doi.org/10.5772/intechopen.95293*

### **Author details**

Maria Teresa Herdeiro1 \*, Tânia Magalhães Silva1 , Inês Ribeiro-Vaz2,3, Eva Rebelo Gomes4 , Adolfo Figueiras5,6 and Fátima Roque7,8

1 iBiMED - Institute of Biomedicine, Department of Medical Sciences, University of Aveiro, Aveiro, Portugal

2 Porto Pharmacovigilance Center, Faculty of Medicine of University of Porto, Porto, Portugal

3 Center for Health Technology and Services Research (CINTESIS), Faculty of Medicine of University of Porto, Porto, Portugal

4 Allergy and Clinical Immunology Service, University Hospital Center of Porto, Porto, Portugal

5 Department of Preventive Medicine and Public Health, University of Santiago de Compostela, Consortium for Biomedical Research in Epidemiology and Public Health (CIBER en Epidemiología y Salud Pública - CIBERESP), Santiago de Compostela, Spain

6 Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain

7 Research Unit for Inland Development, Guarda Polytechnic Institute (UDI-IPG), Guarda, Portugal

8 Health Sciences Research Center, University of Beira Interior (CICS-UBI), Covilhã, Portugal

\*Address all correspondence to<EMAIL_ADDRESS>
© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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## Section 2


**8. References**

An anti-microbial finish for textiles involving skin contact will need additional safety data concerning this aspect. For manufacturers with biocides with relatively low volumes the cost of generating the necessary data may make ongoing production uneconomical. Acute toxicity data is relatively cheap to generate but sub-acute and other long-term studies are very expensive. It is therefore likely that the number of biocides being produced in the future will diminish and bringing new products to market will be even more expensive. A possible future development would be the micro-encapsulation of biocides. The potential is considerable if the correct performance and economics can be achieved. Benefits could include better durability and greater safety. The search for more cost-effective testing

Overall the need for anti-microbial and hygiene finishes looks set to continue for the foreseeable future. Improving performance and cost-effectiveness, while meeting environmental and toxicity requirements, will continue to challenge those working in this

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**7. The future**

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**20**

*India*

**Silver Nanoparticles:**

**Real Antibacterial Bullets**

G. Thirumurugan and M. D. Dhanaraju

*Research Lab, GIET School of Pharmacy, Chaitanya Nagar, Rajahmundry, AP*

One of the first and most natural questions to ask when starting to deal with nanoparticles is: "why are nanoparticles so interesting"? Why even bother to work with these extremely small structures when handling and synthesis is much more complicated than that of their macroscopic counterparts. The answer lies in the nature of and unique properties possessed by nanostructures. Nanoparticles possess a very high surface to volume ratio. This can be utilized in areas where high surface areas are critical for success. Over the past few decades, Metal nanoparticles, whose structures exhibit significantly novel and distinct physical, chemical, and biological properties, and functionality due to their nanoscale size, have elicited much interest. Especially in biological and pharmaceutical sector nanostructure materials are attracting a great deal of attention because of their potential for achieving specific processes and selectivity. Decreasing the dimension of nanoparticles has pronounced effect on the physical properties that significantly differ from the bulk material. Moreover, there are several reasons for the use of silver nanoparticles in nanotechnology as well as in medical and pharmaceutical field. (i) First of all, silver compounds have been used in medicine throughout the history of civilization. (Patra, 2008; Klasen, 2000; Lansdown, 2002) (ii) It is easy to synthesize silver nanoparticles by several simple, economically cheap, safe and reliable methods such as wet chemical, physical and biological; (iii) it can be synthesized from sizes of 2–500 nm by changing the reaction parameters; (iv) it can be easily synthesized with different shapes (spheres, rods, tubes, wires, ribbons, plate, cubic, hexagonal, triangular) using templates and changing reaction conditions; (v) due to the presence of a negative charge on the surface, they are highly reactive, which helps to modify the surface of silver nanoparticles using several biomolecules. Due to the strong interaction between the metal surface and thiol/amine containing molecules (organic molecules, DNA, protein, enzyme etc.) the surface of SNPs can be easily modified; (Bhattacharya, 2007) (vi) SNPs can be easily characterized due to the presence of the characteristic surface plasmon resonance (SPR) bands; (Daniel and Astruc, 2004) due to the presence of a unique optical as well as electronic behavior, these metal particles can be used in biosensors and molecular imaging; (Oghabian, 2010) due to its strong antimicrobial activity, it has found variety of

**1. Introduction**

application in different fields (Fig. 1).