Management problems

Management problem is one of the major issues that affected many industries in earlier days and even today. Problem usually comes up with time which at time can be severe. It appears in varying degrees of severity. Problem should be identified so that they can consequently be solved and this can make a difference in the world. Management problems can bring about down fall of an industry since management is the basis of good industrial growth.Thus why there are quite a number of management problems which were diverse in time prior to industrial revolution as compared to modern time. In today’s industrial management, management problems are not quite many due to upcoming technology which helps the managers to deal with these problems accordingly in regard to management.Industrial revolution changed people’s earlier ways of making various products such as weaving, making of hand tools and other industrial products to use of machines with the help of manpower to make same p roducts by use of different method of manufacturing. The changes which brought about industrial revolution are things like invention of machines which replaced the work of hand tool, steam was invented which was used in various industries to replace the use of muscles in human beings and animals and also adopting the factory’s system of operation.Therefore, due to these drastic changes, management was quite an important aspect in running these industries. In the time of cottage industries, they did not have any manager since the industries were small scale based industry which did not require any management strategies. Incase of those industries which were operated in small shop, they had managers but they were faced by a number of managerial problems.The early industries faced a lot of problems especially in management which was coupled with improper planning since the industries were quite small and those who operated them did not have diverse knowledge on various managemen t strategies used in today’s industries. There was no complexity of operation and thus why managers who in most cases were the owners of those businesses felt that they had little to do in regards to management issue in those industries.In older days before industrial revolution most of production of industrial products took place at homes which made those who operated those productions to have no management strategies since their aim was just to produce the products that they needed and sell them locally which actually did not require any management strategies (Kelvin, N., Encyclopedia of Management 2006). Producers in time before industrial revolution used small hand tools in making simple products and therefore most of their operations were quite simple and did not require anyone to be the controller of those activities since only simple products were manufactured using these tools.Therefore, when the industries started revolutionizing various problems were faced since man agers did not have enough potential to manage since they did not have these strategies. The industries started growing slowly which replaced the simple tools with complex machineries and this resulted to production of more products and since they could be sold in various markets which brought about a need to have managers so that all the operation of the industries could be managed from production to marketing of product. There were quite a lot of problems faced since there were no ready trained or experienced managers to handle the position.In early industries, the managers were faced with statistical problems since they did not have any records kept for their small industries and they did not have advanced managerial procedures which could result to keeping accurate statistics in regard to the products that they were producing. Lack of proper statistics in regard to their small industry progress did not help in establishing the progress of these industries and thus why most of the m could cease to function at any time.They also did not keep the receipt of the things they sold since they sold most of their things locally and they did not value the aspect of keeping records. Due to lack of proper or no management in these small industries they did not keep records of their supplies and therefore they could not realize whether their industries were running at a profit or loss. (De, P.K, Project Termination Process in Indian Industries 2001; 19(2); p 125).Since most of the industries were home oriented there was no complexity of operation and therefore most of the owners could run the daily tasks of those industries independently or with the help of family members. These members did not have any managerial skills in them and therefore they just worked without any guideline of operation. When the industries started to grow, there was great need of proper management since the complexity of the industry increased and therefore operations needed to be managed.Employe es in those small industries like in shop where some of the management strategies were initiated motivation since most of the work was done using simple tools and therefore less work could be realized which resulted to poor pay (Canback & Staffan, Management Consulting Logics, 1998; 9(1); p.32).Therefore employee lacked motivation since the total output of their work was low. Due to this, managers could not be able to organize the workers since they were not motivated to work and this eventually lead to low production of the products in those industries.Early managers essentially lacked management theories which cold govern them on how to handle these small industries in order to uplift their standards of operation. The managers also had low experience which made them not to be aware of some of the managerial skills which can be established in these industries. Due to lack of these aspects managers valued workers as just an object of making profit for their industries. But due to th e fact that these workers can not be programmed, they eventually developed various needs and desires which were to be met by the organization and this brought about a need to have qualified managers.Increased competition in those industries posed great problems to the managers since they did not have potential to handle big enterprises and now with the emergence of these big industries, managers had to look for various ways to develop theories which could help in carrying on with the management issues of the industries.Competition challenge by manager was brought about by the in ability of the managers to reward the employee accordingly for the work that they have done which is basically by paying high wages to workers. If managers had strategies of rewarding employees and appreciating their work, the general output of their products could be increased. Therefore, workers should be given the wages that they deserve for the work that they do since the output.Managers also lacked expo sure since the cottage industries were quite small and therefore even those who managed those industries did not acquire much on management strategies. Exposure to these aspects gained by the quite essential since experience is essential aspect of management strategies.There are a number of similarities of those problems which were faced during the time of cottage industries and after industrial development by the managers (McGee, Encyclopedia of Management Strategic: Management 2006). These problems consequently affected the industries since they have emerged to be big and therefore, lack of proper management can lead to a down fall of an industry. Management aspects after industrial revolution should be enhanced and managers should ensure that they are well acquitted with all the management skills needed for the industry.In today’s industries, management issues have faced a number of problems due to industrial revolution since the industries are growing drastically which re quires a lot of management strategies. The problem of managing new and large industries is still experienced today since new technologies are coming up day by day that make changes in machineries that are used (Nisar, Problem and Management of Small Scale and Cottage Industry 1987).These changes should ensure that the manager have vast knowledge of the changing technologies so that they can be able to manage the operations of those machineries properly. Enterprises also aim at diversifying and enlarging and this can result to a big problem especially to those individuals who are used to managing small enterprise. These enlargements are as a result of competition and therefore mangers should learn various aspects of maintaining their workers since in a case of steep competition the workers can shift to other industries which have proper management and the strategies are favoring the employees.In the case of problem solving, this is a management problem being faced in industries even today due to lack of proper managerial skills. Problems within an industry can result to poor production and they usually arise as a result of misunderstanding between the managers and employees mainly on division of duties and workload of the employees in relation to the relative pay that an employee receives.Managers encounter these problems since they usually want to realize a lot of output than the input. Due to lack of important aspects of management such as paying their employee in regard to the work that they carry out that is to exercise the act of fairness in an industry which is an essential aspect of the management skill required by in an institution or industry.During the times of cottage industries, competition created serious problems to the industry sector managers since they had a big problem of rewarding employees according to the work they does. After industrial revolution many industries came up and therefore the managers have extra task to deal with the steep com petition in various industrial sectors (Ford, Managing and Marketing Technology 2001). Some managers due to monopoly of industries do not have aspects of dealing with competitive marketing ability of the industries. Therefore due to lack of these aspects, the relative output of industry is not experienced.Some managers even in today’s industrial set up have low experience and management theories since most of the industry owners want to employ those individuals with low experience in fear that if they employ those experienced individuals the salary would be high and therefore they end up employing people with low experience or managing their industries themselves without being aware of the relevant theories which are needed in management of industries. Owners of industries should ensure that they employ individual who are experienced in industrial set up and also have management theories so that they can run the industry as per expectations of the owner.Ignorance in managemen t is one of the aspect managers of various faces during their mission of carrying out management strategies in various industries. Assuming some small aspects of management can result to total loss in an industry and this is usually as a result of ignorance by managers. For example, managers should not feel that they are quite superior to the employee and fail to accomplish some of the issue that they put forward. This should be encouraged since employees are the only people who are aware of various problems that industries face since they are the main operator.Therefore, to alleviate these management problems of day to day running of industry the new technology which has been introduced in various industrialized countries should ensure that they use this technology to manage their industries accordingly (Gordon, Industrial Development 1998; 28(3), p.157).Technologies used to manage industries include things like internet, computer and other electronic devices which can be used to m anage industries by keeping appropriate data of the country.Through learning of relevant managerial skills, modern managers ensure that employees are the core of decision making since they understand how the industry is running better. This is enabled by motivating them by giving them their dues appropriately what they deserve. Therefore, through technology it’s believed that these problems will finally end.Reference:De P. K., (2001), Project Termination Process in Indian Industries, International Journal ofProject Management, 19(2), pg 119-126.Kelvin N., (2006), Encyclopedia of Management, Michigan: Thomson gale.Canback, Starfan, (1998), Management Consulting Logics, Journal of Consulting Management,9(1), pg 19-38.McGee J., (2006), Encyclopedia of Management Strategic: Management, United State:Blackwell.Nisar A., (1987), Problem and Management of Small Scale and Cottage Industry, Hawthorne:Deep and Deep Publishers.Ford D., (2001), Managing and Marketing Technology, New York: Thomason Learning EMEA.Gordon A., (1998), Industrial Development, Journal of Contemporary Asia, 28(3), pg 134-176.

Law reform regarding Animal Welfare Essay

As the world changes so do worldviews and therefore, so do the accepted morals and values of the time. With these changing morals and values come altering laws, amended or renewed to reflect these changing views. This is called law reform, in particular, the subject of Animal Welfare. Laws in relation to animal welfare have been made and amended to restore justice and equality to the voiceless members of society. Before recent times, the rights of animals had been severely overlooked. Attention has been brought to breeding and slaughtering practices around the world through wide scale media. In such countries these processes fly under the radar and are rarely monitored, until now. This is when worldwide regulations have to be put in place to ensure that appropriate and adequate treatments are adhered to around the world. Most animal cruelties on a small scale are kept quiet, and are performed either in secluded areas away from prying eyes or those who witness such things are unable or unsure of how to seek justice. Although most of the first laws regarding animal protection from human mistreatment were made in the early 19th Century, according to Peter Sankoff and Steven White’s book; ‘Animal Law in Australiasia’, these laws fall short of bringing adequate justice to the cruelties within Australia and New Zealand. Activists, academics, law professionals and many others share this view, giving even more reason to amend relevant legislation to cover any discrepancies and loopholes. Animal law has only recently emerged as a studied genre of law, which means it is slowly becoming more known. The constitution is the basis for all Australian law and in this case, particularly from section 51. Firstly, section 51 of the Constitution provides that the ‘Parliament shall†¦ have power to make laws for peace, order and good government of the Commonwealth with respect to’ 39 subject matters, known as ‘heads of power’. Although the constitution itself doesn’t outline laws regarding animals other than fish, it does give the conditions in which other laws can be created. The Commonwealth can enact any law, provided that the law is characterized as being under at least one of the heads of power. Subject to some limitations, a law that is characterized as being one with respect to one of these heads of power will be valid although it may regulate some other matter that is not specifically allocated to the Commonwealth (such as animal welfare). Through external affairs powers and corporations power came these treaties: Examples of the treaties form ed with other countries are as follows: * The Convention on Biological Diversity 1992, * The Convention on International Trade in Endangered Species of Wild Fauna and Flora 1973, * The Convention on the Conservation of Migratory Species and Wild Animals 1979 (‘the Bonn Convention’) and * The Convention on the Conservation of Nature in the South Pacific 1976 (‘the Apia Convention’). Mechanisms of Reform- Non-Government Organizations. ‘Lawyers For Animals’ is an organization dedicated to advocating the need to improve animal welfare through education and law, as well as ‘Voiceless’. Voiceless is a non-profit organization dedicated to fostering networks for law professionals, academics and politicians to influence law and the need for law reform regarding animal welfare. They conduct research regarding agricultural industry practices, exposing legalized cruelty and promoting need for debate. They also attempt to inform the public about consuming and which products have and have not come from low quality, quantity breeders. They recognize the need for a voice that projects the facts of cruelty among everyday people and corporations that give way to law reform and law making in relation to the protection and rights of animals. By building a forum, social justice movement, funding in education, participation in events and forming relationships with law schools and firms, Voiceless hopes to pr ovoke change and awareness about animal welfare. The key issues that have been addressed as contemporary issues regarding this subject are; * Animals as property * Animals in agriculture * Animal welfare legislation * Labeling * Live animal export * Intensive livestock production and climate change * Animals used for scientific purposes * Animals used for entertainment * Pets * Pests * Wild animals * Fish and crustaceans These are a vast range of issues, which call for a vast range of bills to be introduced from a large number of interested politicians. Having animals as property and pets, means that we as humans own them. We dictate what it is they eat, drink, do etc. We are responsible for taking care of them, and the blatant fact is that many people don’t. As Gary Francione, ‘distinguished professor of law’, states – animals are ‘as a matter of law, solely means to human ends. As such, their value is measured in terms of their usefulness to humans, and not in terms of their own interests’. The Animal Legal Defence Fund (‘ALDF’), was established in 1979 and has more than 100,000 dedicated lawyer members who apply their skills in a number of ways in order to protect the lives and advance the interests of animals through the legal system. For example, the ‘Litigation Program’ files cutting-edge lawsuits to stop the abuse of companion animals, and animals abused in industries including factory farming and the entertainment business; while the ‘Criminal Justice Program’ works with law enforcement and prosecutors to seek maximum penalties for animal abusers. ALDF has also been at the forefront of law reform in respect to one that can actually make a difference. With changing times also comes the once described as ‘likely to be the next great social justice movement’, animal welfare is becoming more well known. Universities have been reflecting this growing issue, providing more and more opportunities for education on and relating to animal rights and animals and the environment. Examples of such debates for reform topics and their respectable supporters ( as found on http://www.alrc.gov.au/news-media/2008/will-‘animal-rights’-become-next-great-social-justice-movement) a re below: * Arguments in favour of basic legal rights for nonhumans (Steven Wise; President, Center for the Expansion of Fundamental Rights Inc., Coral Springs, Florida, USA ); * Suicide foods’: the anthropomorphising of animals (Prof Mark Kingwell, Uni of Toronto); * Animal rights activists’ case against the animal industries (Tom Regan, American philosopher and animal rights activist); * The philosophy behind animal welfare (Geoffrey Bloom, Geoffrey Bloom & Associates); * The law and pig farming (Dr Malcolm Caulfield, legal counsel for Animals Australia); * Animals and the law in Australia: a livestock industry perspective ( Kathleen Plowman; General Manager Policy for Australian Pork Ltd, with Alan Person and John Topfer); * The treatment of feral animals (Graeme McEwen, Barristers Animal Welfare Panel); * The ethics of animal biotechnology (Professors Mickey Gjerris and Peter Sandoe, University of Copenhagen); * Animal derived food labelling (Katrina Sharman, Corporate Counse l, Voiceless, the fund for animals); * The common law and animal rights (Nichola Donovan, Lawyers for Animals); * Animals, guardianship and the local courts Another benefit human’s get from animals is profit. Breeding and meat production are industries where greed comes into play and animals needs and rights are forgotten. These NGO’s raise awareness and with the help of media, put pressure on the courts and parliament to introduce change. Certain ministers will be targeted and issues put forward to so that agencies have a representative in court. Animal Laws that already exsist: * Animal Welfare Act 1992 (ACT) * Animal Welfare Act 1999 (NT) * Prevention of Cruelty to Animals Act 1979 (NSW) * Animal Care & Protection Act 2001 (QLD) * Animal Welfare Act 1985 (SA) * Animal Welfare Act 1993 (TAS) * Prevention of Cruelty to Animals Act 1986 (VIC) * Animal Welfare Act 2002 (WA The shortcomings of these laws are the lack of equal treatment among animals used for scientific research and those that are pets. Eg: Cats will receive better treatment than pigs, as they are pets and pigs are used simply to grow and once they are grown, to eat. Again, seen as property beneficial to humans, which goes against the rules of law. The majority of the difficulties with enforcement stem from the manner by which the power to enforce animal welfare legislation is granted. The power is granted to: * State government departments; * the RSPCA; * and the police. Much of the enforcement is carried out by the RSPCA. It is the state and territory governments that are responsible for enacting legislation appropriate to their areas, therefore this will be done through the New South Wales Law Reform Commission. The New South Wales Law Reform Commission takes care of localized matters in relation to the state and the Australian Law Reform Commission takes care of matters to do with international treaties of trade and animal treatment. The New South Wales Law Reform Commission may be the pinnacle of law making bodies for New South Wales, The Australian Law Reform Commission itself recognizes the altering times and calls for change throughout the country. Dated 19th May 2009, David Weisbrot, President of the ALRC spoke at the University of Sydney about their views upon the issue, with the NGO ‘Voiceless’. He stated that; â€Å"I think we need; national – or at least harmonised – legislation that protects animal welfare; and is not set at the lowest common denominator; or is so riddled with loopholes that you could drive a large factory farm truck though.† From the President of the ALRC itself, one would have to assume actions were being made in establishing new laws regarding animals, however it is not so. In the recent years, there has been much talk of changes yet no actions or amendments have been put in place as a follow through of this talk. David also stated that we evolve over time, resulting in the need for law reform and that it is this slow and painstakingly gradual task. Reasons for law reform regarding animal welfare: An example of the altering views are prime in the subject of Sweden banning importations of Australian wool in the fear that it would be supporting mulesing. This could go on to be a major issue for the wool trade industry. Another concept is that of the changing and growing world, as the population grows, so does the need for food. This pressures farmers into states of mass production; Eg: The mass breeding and steroid use in chickens so that they reach adulthood 10x faster than usual, leaving their legs to break and mutate under the abnormal weight that grows too fast for the rest of the body to keep up. These chickens have shorter and extremely painful life spans, are kept in battery cages where there is no room for them to walk or sit. This issue has been addressed in documentaries attempting to make the public aware of the cruel and selfish origin their produce is coming from and spur politicians into addressing the subject with observance of practices and laws to protect such a nimals. As is seen in the many above genre’s relating to animals as pets, food and many other things, a massive need for appropriate and widespread legislation has surfaced. Ways of mass production are under complete scrutiny for cruel practices, while more monitoring of animal owners has become paramount for the RSPCA. Universities have opened doors to educating the worlds youth about this topic, providing a new force of law trained individuals, able to influence people within their league into the advertisement and hopeful altering of current laws. These trained professionals have the ability to uncover the shortcomings of current laws that have been so far swept under the rug, and take them to members of the State and Federal Governments for consideration. The Non-Government Organizations such as the RSPCA or Voiceless project widely held views of the public, who may not be as educated or influential within the political spectrum, but allow the public a say all the same. With a new influx of technology from the late 20th into modern 21st century, brings both positive and negative possibilities when monitoring and even bringing about animal cruelty. That is, one can use cameras placed in chicken farms to monitor such breeding, but it is the development of scientific technology that has allowed such abnormal growth in the first place. Education towards use of technology in a morally aware way should be a priority for the government, as well as making the public more aware of those cruelties that happen every single day. By making the public largely aware of various aspects of animal cruelty, many more opinions can be altered to support the work of the RSPCA and Voiceless, so that both the N.S.W Law Reform Commission and Australian Law Re form Commission can alter their own priorities and make changes to relative legislation. Bibliography: * http://www.daff.gov.au/animal-plant-health/welfare * http://legal-dictionary.thefreedictionary.com/reform * http://www.lawyersforanimals.org.au/documents/Animal-Law-Subject-Proposal.pdf * http://lawyersforanimals.org.au/ * http://www.federationpress.com.au/bookstore/book.asp?isbn=9781862877191 * http://www.animallaw.info/nonus/articles/ovaustrailia.htm * http://lsa.net.au/wcb-content/uploads/lsa/files/2011/Animal%20Law%20-%20a%20need%20for%20reform%20(LSA%20State%20Conference%20March%202011).pdf * http://www.alrc.gov.au/news-media/2008/will-‘animal-rights’-become-next-great-social-justice-movement * http://www.alrc.gov.au/news-media/2009/voiceless-animal-law-lecture-series

Synopsis of a Phrase: You Don’t Know What You Have Until It’s Gone

â€Å"You don’t know what you have until it’s gone† Like an old saying â€Å"You don’t know what you have until it’s gone†. For some people these are just words, but for others it’s really more a life changing phrase. To me this phrase are more than just words. I question myself every time I see or hear about mother’s abandoning their children’s. I really can’t understand what come across their minds to make a life changing decision. Every woman who has the blessing of having children’s should be grateful, because not every woman has the glory of giving birth.I can’t comprehend leaving behind a part of you like if it didn’t exist, that is just outrages. But then again life in some way or somehow it comes back and haunts you, it’s all about karma. This is where the old saying of â€Å"You don’t know what you have until it’s gone†, kicks in then it’s too late to try to regain what you had back then. As I grew up as a teenager I always had in mind that I wanted to have a boy first and then a girl as my own children. Well, God heard my wishes and made them true, but not knowing that later on in my life I was going to wish that I hadn’t made that petition.I had my son at age 17 and my daughter at age 19, years passed by and simply no more pregnancies came along. I was divested as well as my husband we wanted to have more family. Apparently it just wasn’t going to happen I was diagnosed with PCOS (Polycystic Ovarian Syndrome). The possibilities of getting pregnant were between 2% to 5% which let’s be honest, â€Å"Not enough†. Pretty much I become infertile, but I had set my mind if these are Gods wish let them be. I was already so grateful in having my two kids. I’m not going lie I still had that wish of becoming mother again back in mind.I have a sister who had a beautiful daughter two years ago. I was hopi ng for my sister to change for good, since she was more into going out with friends, boyfriends, and anything relate to being irresponsible. The first year seemed to be okay even though she still went out. In the beginning of the second year she started to complain about having her daughter. She would say, â€Å"I wish I have never had you†. How can she possibly say this, she is only an â€Å"innocent little girl† who didn’t ask to be brought to this world. I spoke to my mother about this situation.I simply couldn’t let this go on. My mother said, â€Å"I will not let this happen again†. My mother did actually speak to my sister, she obviously didn’t like that so she called me up and said, â€Å"I’m leaving the house and I’m giving the baby away to someone†. I said â€Å"No you are not†! Give her to me, I said. My sister answers back by saying, â€Å"Well, come for her now or I will give her away†. So I eag erly left to my mother’s house. I had to tell my sister, that I hope you never ever regret what you are doing. This is when I brought up the old saying, â€Å"You don’t know what you have until it’s gone†.Some day you will be begging for the forgiveness of your daughter and this is when you will realize that what you did was wrong and it will be to late. At the end I tried to understand why she took this decision. What was going thru her mind? I just can come with an answer. I’ve tried every possible method of getting pregnant and here she comes and leaves her daughter like nothing as if she never carried her in her stomach for 9 months. By the way I was present in the baby’s birth. It was wonderful reliving the moment when I gave birth to my children.Now I’m going thru the moment of seeing my niece being abandoned by her insensitive mother. This really breaks my heart by seeing my little niece looking for her mother and not finding h er. To me this kind of people should not have the blessing of being a mother, if in some way you can call them mothers. While other women try and wish they could be mothers. We should have more conscious in what we do and the consequence that later in life will bring us. We should treasure what we currently have and not wait until it’s too late to realize what slip away from our hands. Life is to short to make wrong decisions.

Personal Statement, My Personal Experiences Essay

Personal Statement, My Personal Experiences - Essay Example His ambition for his children has often placed me in challenging positions. The most challenging of these was when, following the completion of my secondary education, he decided to transfer me to SMUK-1 BPK Penabur, the most difficult and best high school in Indonesia. I did not want to transfer and quite honestly, did not feel that I was capable of succeeding in such a competitive and tough educational environment where students where, to a large degree, expected to rely on themselves for success or failure. The environment, being so very different from what I was accustomed to, frightened me and for much of my first high school year, I was miserable. It was, within the limits of my experience, a period of tremendous intellectual and psychological hardship. Besides being extremely competitive and difficult, I had no friends at SMUK-1 BPK Penabur. There was, therefore, no one to guide me through this period and, at the same time, my father demanded nothing less than excellence. All I could do, therefore, was accept the situation and apply myself as I had never in my life done. While I recall this as a miserable year, the fact is that I succeeded and achieved the grades demanded of me. More importantly, I discovered that nothing is really ever too difficult. (2) As Indone

Contempary issues in change management - Major Assignment Essay

Contempary issues in change management - Major Assignment - Essay Example s for inculcating a new change management organizational culture that has, at its core, the process robust knowledge management which ensures a healthy employees’ participation through the concepts of employee empowerment and employee motivation within the ambit of a transformational approach to change management. The very first important step toward creating a change management system within any organization is the thorough assessment of the organization culture, to assess the level of change management maturity level. Such a change process will transform itself into competitive advantage only when it is properly captured, inculcated and shared and of these the very important step being the capturing of the change management system. Capturing of such a system as a dynamic snapshot -particularly in high value selling environments like the one prevailing in the Corporate Express Australia Ltd (the organization under reference) and which is at the centre of this research is highly problematic as the nature of tasks and activities within these organization are very unpredictable, complex and dynamic, dynamic in the sense because of constant, recurrent and reorganization of the organizational targets and objectives to match changing environment. Changing environment warrants capturing of knowledg e and knowledge management within the organization. Thus one should have an organizational culture that leads to the maximum capture of the environmental and business specific knowledge; ensures its total assimilation and utilizes it in making time specific effective decisions that maximize the value for the organization in its value chain-which can be interpreted in financial terminology in terms of profits and turnover on the one hand and improved or enhanced employees’ productivity and satisfaction, on the other hand. Thus organizational culture and knowledge management systems can be used as tools to target above financial and employees’ specific variables under

Fundametals of pedagogy assignment Essay Example | Topics and Well Written Essays - 2500 words

Fundametals of pedagogy assignment - Essay Example A significant factor concerned in meeting these objectives is motivation. If learners are not motivated in one way or another, then it is most expected that little or no learning will occur, or, if, by any chance, some learning occurs, then it is likely that it will not be retained for future use. Educational theories have great influence on educational structure. In order to capitalise on the success of individual and school-wide, classroom teaching programs, teachers and school administrators should consider students needs, as well as their hierarchical order (Mead, 2009). This should be a top priority in the creation of such programs so that learners can have the ability to reach their most prime level of potential. For instance, if a learner/student does not feel comfortable with the class-room environment, his/her classmates, feels hungry, then the student/learner will not be in a capacity to concentrate well on learning. The student will be preoccupied with these agitations. A number of learning theories (social learning, Behaviorism and Jean Piaget among others) can rectify this as they can help a student understand the best way they can learn in order to make education effective to them (Tough, 2003). Learning is one of the most significant actions in which humans partake. It is the central goal of the educational procedure, even though most of what individuals learn happens outside of school. Comprehending any theory needs a clear thought of what the theory is trying to clarify. When a certain word is applied, individuals normally think everyone has a similar understanding of what the word signifies. Sadly, this is not the case always. In trying to comprehend the numerous theories of learning and their effects to education, it is useful to understand that the phrase â€Å"learning† means diverse things to diverse people and is applied fairly differently in diverse theories (Tough, 2003). As theories of learning developed over the past half-centu ry, descriptions of learning modified from transformations, which happen in the brain or actions of a person to changes in participation in enduring activities with other people to transform in an individual’s identity in a group (for instance, a change to being a leader from being a follower). Even though, a majority of definitions of learning entail a change in a person’s knowledge, capacity to carry out a skill, or take part in an event with other people, there are significant differences among the theories concerning the nature of this amend (Tough, 2003). This paper will apply two educational theories – social learning and behaviorism – to an educational experience that I have associated with and critically examine how well these two theories account for that experience. Social Learning Mary, a 37 year old Nigerian woman living with HIV/AIDs, was acknowledged by From the Ground Up – a group that is involved in building HIV/AIDs programs to hel p both those who are affected, as well as infected with the virus – for her outstanding service who elevate people from the illness. Her story mainly reflects the social learning theory (peer education), which I find extremely significant to associate with as HIV/AIDs is a disease that has affected many in our world today. Mary states that her personal

Issues in Global Business and Consultancy Essay

Issues in Global Business and Consultancy - Essay Example The choice for those locations is due to the technological advancement and industrial production and as part of the globalisation strategy. As a result of the globalisation and to its contribution to the worldwide healthcare needs, the company ranks among the research–oriented healthcare and pharmaceutical companies in the world. Indeed, this has made the company to play a leading role in making sure that the global population remains healthy. As well, the company benefits from its global business approach, and enjoy Comparative Advantage, Absolute Advantage Fallacy, Endogenous Advantage, and Bilateral Trade Patterns, due to the nature of its production. Table of Contents Executive Summary 1 Table of Contents 2 Introduction 3 Brief Research Methods 3 Globalisation 4 Globalisation Challenges and the Company’s Interventions 6 International Trade Theory 7 Comparative Advantage 7 Absolute Advantage Fallacy 7 Endogenous Advantage 8 Bilateral Trade Patterns 8 Recommendations 9 Conclusions 9 Bibliography 10 Appendix 11 Introduction Global business and consultancy are the major considerations for companies seeking success. There are certain issues affecting business operations, which have to be predetermined, analysed for the good of the business. In this report, the major issues to be discussed include globalisation and International Trade Theory relating to GlaxoSmithKline Company (GSK). The company was formed in the year 2000 when Glaxo Welcome Company and SmithKline Beecham merged (Weysig, 2004, p.16). Since the company is international based, operating in more than 100 countries, all the factors in the global business arena has an impact on it s operations. As any other company, GSK has internal and external challenges because they manufacture health products. Therefore, millions of people are depending on the products for their health needs, meaning that an outbreak of epidemic disease creates an impact of increase in the demand of the products. Int ensifying their research is the key to the company’s development. Some of the globalisation factors affecting the company include is he demand arising from low income countries. As a leader, they have the mandate and compulsion to fulfil their mission despite all the global challenges. Brief Research Method During the study, the researcher employed a deductive approach in doing the investigation. First, the researcher formulated the topic of discussion, under which the problem to be investigated was stated. Secondly, literature review followed, in which the divergent views of different scholars and other relevant company information was incorporated. Third, the researcher proposed the theory to be used in the company analysis, and designed the research to test the theories. Finally, the researcher started the study by collecting data, analysing them, using qualitative and quantitative techniques, after which the findings were presented. Globalisation The company is based in t he United Kingdom, with branches in more than 100 countries distributed across the world (Feenstra, 2003, p.44). The other important aspect of the company to note is that, the UK, US, China and Belgium host the major research centres of the company (Feenstra, 2003, p.45). Due to its contribution to the global health needs, the company is categorised

Critical Analysis Paper Essay Example | Topics and Well Written Essays - 1750 words

Critical Analysis Paper - Essay Example Moreover, Chaffee’s The Philosopher’s Way discusses the various philosophers’ view of the world, the nature of reality, and the truth (2012, 51). By using Kants Categorical Imperative and utilitarian views, morality is relative to humans’ rationale of right and wrong. Immanuel Kant’s Categorical Imperative Kant is the main proponent of a critical type of philosophy known as the categorical imperative. Human beings have the tendency to evaluate their actions based on their emotions towards the acts they committed. This means that it is hard to assess the goodness or badness and rightfulness and wrongness of an action because of the difficulty to find a basis for logically and objectively judging this particular action. Kant helped us in understanding and explaining our actions and decisions based on a given principle known as a priori judgment, in which all knowledge presupposes an experience. It is in this line of thought that Kant differentiated mo ral judgments from empirical ones. Empirical judgments refer to judging facts of which experience teaches us, while moral judgment tells us what we ought and not ought to do. Empirical judgment does not relate to the understanding of moral action. What Kant meant by a priori judgment also entails a judgment of necessity which judges an act based on universal standards of right and wrong, such as stealing is wrong in any circumstances. Categorical Imperative is considered by Kant as the universal principle of justice that right is superior to good applicable to the whole universe. He postulates that humans must act based on universally accepted maxims which also apply as laws for all of the humanity. Kant believes that moral rules are universal. Therefore, what is allowed for a single person is also allowed for everybody, and what is prohibited for one is also prohibited for the rest. Moreover, what is obligatory for one is also obligatory for the rest. He also acknowledges freedom o r autonomy along all individuals, but this autonomy must rest on positive values and will serve as a guiding law for all our actions. The word imperative in his philosophy provides us with some sort of restriction which limits our actions that are grounded on personal interests and selfishness which moral rules considered universally wrong. Simply saying, actions that are morally wrong universally regardless of the means or ends are considered to be morally wrong and nothing else, while morally right actions that are universally accepted are also morally right. In other words, Kant suggests that life is composed only of two colors, black and white, and that there is no extent to which an action can be considered better or worse because it only falls into two categories. White lies are wrong under any circumstances because they are still considered as lies, and lying is universally wrong in any event. Principle of Utilitarianism Jeremy Bentham, in his Principles of Morals and Legisla tion, conveys rationality in his analysis of ‘the greatest happiness system’ or the so-called ‘means-end’. Other philosophers describe happiness as a goal, a result while Bentham describes happiness as simply a pleasure without the pain. In other words, people can quantify the value of pleasure or pain depending on the magnitude and for how long. According to Bentham, the overall good of the society is dependent

Where Did Americans Spend Their Money Essay Example | Topics and Well Written Essays - 250 words - 1

Where Did Americans Spend Their Money - Essay Example According to the research findings, it can, therefore, be said that in his findings, Sparshott reveals that restaurants and retailers witnessed a sales rise of 1.2 percent in June compared to the previous month. The big vehicle sales also helped boost the level of economic growth. Dealers of motor vehicles and spare parts indicated that they witnessed a 2 percent rise in June compared to May. Even with the elimination of auto sales, gains were broad-based, as they still reflected a 1 percent growth. Furthermore, the cheap prices of gasoline have provided Americans with a windfall, although in recent months they are more motivated to saving rather than spending. In May, however, gasoline stations witnessed their ultimate leap since 2012, although Americans ignored the move. They directed their earnings to gardening and building materials, non-store retailers, and clothing stores. Thus, based on the growth in sales in the recent months, the researcher has realized that Sparshott has ef fectively shown the way the American economy is shifting from the harsh weather witnessed during the first quarter of the year. This is because the present figures are revealing strong growth in payroll real income. This way, the author hopes the country will be able to reverse the contraction it witnessed during the first quarter of 2015.

Toyota Term Paper Example | Topics and Well Written Essays - 1000 words

Toyota - Term Paper Example The accelerator issue gradually turned to be one of the engineering defects with the vehicle’s software that caused the poor response of the pedals. It was not a simple issue for defective floor mats (Spaller, Willms, O’Connor & Daniels, 2014). Further, the controversy developed from Toyota amounted to delays in public response and action from Toyota following the accident. In most cases, the matter was downplayed by public informing and news releases from Toyota’s management. The absence of urgency from Toyota’s part was an illustration of poor handling and management of previously unseen risks resulting from poor planning. There are various ethical issues feeding into from the accelerator recall. In recent years, Toyota gathered a reputation for safe and reliable vehicles. The defective pedals raised concerns, and Toyota sought to surpass and grow General Motors as a global performer in the automobile company. The desire to advance growth called for an expansion of manufacturing plants from home country, Japan (Spaller, Willms, O’Connor & Daniels, 2014). This resulted in the expansion of the capacities of supply. Toyota continues to pride itself on â€Å"genchigenbutsu† and â€Å"kaizen† principles that translated to â€Å"continuous improvement† as well as â€Å"inspecting problems from the source†. Toyota’s reputation and culture for excellence coupled with cultures of hesitance to take up the responsibility in the rise of accidents. Establishing a warning label such as â€Å"Accelerator may stick, apply caution† on its vehicles would be negligent on Toyota’s part as the users of the automobiles were put at fatality risks in defective vehicles. Caution does not involve adequate cover conditions up of deaths by user within the automobile industry. The firm appeared hesitant to broach ethical issues on its advertising. During the period, Toyota’s advertising

Uneasiness Due to Less Commanding Novice Physical education teacher Thesis

Uneasiness Due to Less Commanding Novice Physical education teacher - Thesis Example This essay discusses that the experience of the teacher helps the teachers making plans for their lessons keeping in view the characteristics of the class and the attitude of the students. The experienced teacher is able to develop the task for classroom on the basis of their observation of the needs and behaviours of the children but the novice teacher has no or little idea about the attitude and behaviours of the students in the physical education class and their study plans and lessons are mainly based upon the written sources rather than real time observations.After implementing the lesson plans in the first class they have to monitor if there is need of modifying the plans according to the needs of the students. In this situation, the students are not getting refined educational instructions as the teacher has to spend more time on experimenting and testing his lesson plans rather immediately practicing them. The novice teacher often changes their lesson plans and activities on the basis of the class response that causes uneasiness to the students and makes it difficult for the students to easily adjust in the classroom.The decision-making strategies of the novice teacher are also different from the experienced teacher. Unlike the experienced teachers, the novice teacher doesn't have many strategies for managing the students in the class by facilitating their individual performances so the novice teacher mainly focuses upon the interest level of the entire class and make a decision on the basis of the overall interest.

European Court of Justice - Free

European Court of Justice Free Movement of Persons Essay From early on it became clear to close observers of the EU that the role and rule of law were going to be critical in anchoring EU policy regimes. If the legal system could ensure a high rate of compliance, a way of giving authoritative interpretation to disputed texts, and a means of redress for those for whom the law was created, then the EU process as a whole would gain solidity and a predictability that would help it to be sustained. The ECJ was established in the first treaty texts; these have been virtually unchanged since then, except to cater for the increasing workload and successive enlargements of the EU membership. The ECJ, sited in Luxembourg, is now composed of fifteen judges, as well as the nine advocates-general who deliver preliminary opinions on cases. The SEA in 1986 established a second Court of First Instance, composed now of fifteen judges, to help in handling the heavy flow of cases. The EU has thus something like a supreme court, able to provide an overarching framework of jurisprudence, as well as to deal with litigation, both in cases referred via the national courts and in those that are brought directly before it. The Courts sanctions are mostly the force of their own rulings, backed up in some instances by the ability to impose fines on those (usually companies) found to have broken EU law. The T EU gave the ECJ power to fine member governments for non-application of European law. Also, as a result of its own rulings (especially one of the Factortame cases on fisheries see Chapter 13), damages can be claimed against governments that fail to implement European law correctly. The Courts take their cases in public, but reach their judgments in private by, if necessary, majority votes; the results of their votes are not made public, and minority opinions are not issued. A series of key cases has, since the early 1960s, established important principles of European law, such as: its supremacy over the law of the member states, its direct effect, a doctrine of proportionality, and another of non-discrimination. In doing so the ECJ has gone further in clarifying the rule and the role of law than had specifically been laid down in the treaties. In some policy domains court cases have been one of the key forces in developing EU policy regimes. Table 1. summarize the pattern and volume of cases before the Court. Table 1 New cases at the European Court of Justice, 1972-1997 (no.) (five-year, periods, Since 1972; five-year 1992-1997; each year given) Subject-matter Cases 1972 1977 1982 1987 1992 1993 1994 1995    1997    until       1971    Agriculture and 99 36 61 83 81 198 210 65 70 60 66 fisheries Transport 3 2 4 5 14 10 11 5 3 11 Taxation 27 1 2 9 35 20 21 25 36 33 61 Free movement of 53 3 25 56 45 33 58 86 79 50 61 goods and customs Competition and 38 6 10 42 34 54 35 20 35 28 45 state aids Freedom of 3 2 4 12 12 20 47 34 46 39 establishment and to provide services Free movement for 37 11 19 17 35 49 59 44 54 70 51 workers and social policy Environment 15 11 11 42 59 47 Rest a 2 16 21 44 23 43 29 26 54 34 Staff of EU 268 23 25 85 77 9 10 5 15 13 14 institutions b Other(ECSC, EAEC, 25 27 11 9 4 13 4 15 privileges and immunities) All 895 82 162 348 395d 438 486c 347 409 420 444 a Inc. common commercial policy and cases under agreements with third countries. b These are contract and social security cases of EU civil servants, mostly dealt with by Court of First Instance created in 1989, except for appeals to ECJ. This strong legal dimension has a large influence on the policy process. Policymakers pay great attention to the legal meaning of the texts that they devise; policy advocates look for legal rules to achieve their objectives, because they know that these are favoured by the institutional system; policy reformers can sometimes use cases to alter the impact of EU policies; and in general there is a presumption that rules will be more or less obeyed. Hence policy-makers have to choose carefully between treaty articles in determining which legal base to use, and to consider car Efully which kind of legislation to make (Reich Harbacevica, 2003). Regulations are directly applicable within the member states once promulgated by the EU institutions. Directives have to be transposed into national law, which allows some flexibility to member governments, but within limits set by the ECJ. Decisions are more limited legal instruments applied to specific circumstances or specific addressees, as in competition policy. All three kinds of law may be made either by the Commission (under delegated powers), or by the Council, or jointly by the Council and EP (under co-decision). And all are subject to challenge through the national and European courts. The vigour of the European legal system is one of the most distinctive features of the EU. It has helped to reinforce the powers and reach of the EU process, although in recent years the ECJ has become a bit more cautious in its judgments. We should note also that in some policy domains member governments have gone to considerable lengths to keep the ECJ out of the picture. Part of the reason for the three-pillar structure of the T EU was to keep both CFSP and JHA well away from the reach of the European legal system. Even though the ToA goes some way towards incorporating parts of JHA and Schengen more fully within the system, it remains contested how far they will be brought within the jurisdiction of the ECJ. One issue which floats in the debate is how far the other European legal order, based on the European Convention of Human Rights attached to the Council of Europe, is to be linked to the EU, and whether the EU should adopt its own Charter on Fundamental Rights. The wider institutional setting The EU institutional system includes in addition a number of additional organizations that have an impact on, or provide instruments for, EU policies. Some are consultative. Some provide control mechanisms. Some provide autonomous operating arms. Consultation and lobbying The founding treaties established the Economic and Social Committee (and the Consultative Committee for the ECSC) as a point of access to the policy process for socioeconomic groups. Its creation borrowed from the corporatist traditions in some of the founder member countries. It has not, however, become an influential body in the policy process. Instead socio-economic groups have found their own more direct points of access since the 1960s, both through EU-Ievel federal associations and through sector-specific trade and producer organizations. These became even more active in the period around the development of the single European market (Forder, 2002). Individual large firms have also taken pains to develop links with the EU institutions, again some since the 1960s, but many more and with more vigour since the early 1980s. A more recent development has been the increased activity of groups and lobbies representing societal interests, the consumers, the environmentalists, womens groups, and increasingly a range of other advocacy groups and nongovernmental organizations (NGOs). Illustrations of the activities of these different kinds of groups can be found in many of our case-studies (Groenendijk Guild, 2001). The TEU introduced a second consultative body, the Committee of the Regions, in response to the extensive involvement of local and regional authorities in seeking to influence those EU policies that impacted on them. The Committee provides regional and local politicians from the member states with a multilateral forum, and an opportunity to enhance their local political credibility. At least as important, however, is the direct lobbying by infranational (local and regional) authorities, many with their own offices in Brussels. These same infranational authorities also engage in efforts to influence national policy positions and the implementation of Community programmes. Chapters 9 and 13 comment on this in relation to the structural funds and the common fisheries policy. Control and scrutiny In the mid- 1970s concern started to be voiced that the EU policy process was subject to few external controls. The EP at the time had few powers, and national parliaments paid rather little attention to EU legislation and programmes. It was the growing scale and scope of the EU budget and spending programmes that led the arguments about the inadequacy of scrutiny. This led to the creation of the European Court of Auditors by the 1975 Budget Treaty. Since 1978 it has, from its seat in Luxembourg, endeavoured to evaluate systematically both revenue-raising and spending. Both in its Annual Reports and in specific reports it has drawn attention to various weaknesses in the budgetary process, as handled by the Commission and national agencies. Here we should note that about four-fifths of EU budgetary expenditure is disbursed by national agencies. Chapter 8 describes some of the Court of Auditors activities and impact. We note here that many of its criticisms fell for many years on deaf ears member governments that were reluctant to face up to some of the issues, an EP that had other preoccupations, and a Commission which repeatedly undervalued the importance of sound financial management. In late 1998 this situation was reversed by the row over alleged financial mismanagement by the Commission. Another new instrument of post hoc control is provided by the Ombudsman attached to the EP under the provisions of the TEU. The aim is to provide a channel for dealing with cases of maladminstration vis-à  -vis individuals. Thus far the existence of this office has not had a large impact, although it may have contributed to making the policy process a little more open than hitherto. Some control and scrutiny of policy depends on national institutions, both parliamentary and financial. National parliaments had no official recognition in the institutional system until the early 1990s. Each member state had developed its own, mostly rather limited, procedures for national parliamentary scrutiny of EU policy. The same discontent that had led to some strengthening of European procedures started to provoke a debate on national scrutiny. Both the T EU and the ToA mention the importance of encouraging this, although there is little likelihood of standardized procedures emerging. Instead it seems likely that EU-level policy-makers, especially in the Commission, will pay more attention to national parliamentary discussions and appear more readily before national parliamentary committees of inquiry. This heightened sensitivity to country-level preoccupations is becoming a more marked feature of the EU policy process. It may well be emphasized by the establishment of national parliamentary offices in Brussels (by September 1999 from Denmark, Finland, France, and the UK). From market citizenship to political and social citizenship As mentioned previously, 184 it was at the 1972 Paris Summit that European economic integration was put into a broader perspective of social welfare. Since then, the neo-liberal philosophy that was at the basis of the European Economic Community (and still is, to a large extent, at the basis of the European Community, that is, the first pillar of the Union) was gradually turned into a more socially oriented philosophy. From a perspective of citizen rights, this means that the rights that citizens enjoy by virtue of EC law are no longer only â€Å"market rights† but have been enlarged to include â€Å"political rights† as well, and slowly also â€Å"social rights† in the broad sense of the word, that is, rights (and duties) concerned with peoples welfare generally, including work, education, health, and quality of life. 185 This transformation started with the incorporation, by the Maastricht Treaty, of a new part II in the EC Treaty, entitled â€Å"Citizenship of the Union† and composed of Articles 17–22 (ex 8–8e) EC. According to Article 17 (1) EC, citizenship in the Union, â€Å"complement[ing] and not replac[ing] national citizenship, † is established and accorded to every person â€Å"holding the nationality of a Member State.† The rights enjoyed by Union citizens are, according to Article 17 (2), â€Å"the rights conferred by [the EC] Treaty †¦ subject to the duties imposed thereby.† Those rights are in the first place the internal market freedoms (in the exercise of which discrimination on the basis of nationality is prohibited) and related consumer and worker rights specified elsewhere in the treaty. Then, in Articles 18 to 21 EC, a limited number of rights are enumerated, starting with the general right to move and reside freely within the territory of the Member States and followed by a number of specific political rights: the right to vote and stand as a candidate at municipal and European Parliament elections, the right to diplomatic protection in a third country, 186 the right to petition the European Parliament and to address complaints to the European Ombudsman. In Articles 39–46 of the (as yet non-binding) EU Charter of Fundamental Rights, this list of citizen rights was consolidated, and it was expanded with the rights to good administration and access to documents (Peers, 2004). The enumeration of these lists of rights in the EC Treaty, as amended, and in the EU Charter may seem rather symbolic, many of the rights mentioned being already specified in other treaty provisions. However, the fact should not be overlooked that the rights enumerated in Articles 18 to 21 EC are granted to all citizens, that is, they are unconnected with the exercise of any economic activity. That obviously holds true for the political rights, but it is also becoming increasingly true, as we will see below, for the general right of citizens, established in Article 18 EC, to move and reside freely within the territory of the Member States. Among the rights conferred by other treaty provisions are the rights that workers from other Member States, and by extension members of their family (so-called â€Å"dependents†), enjoy in the Member State where they work. These rights remain connected, however, to the status of â€Å"worker† in the sense of Article 39 (1) EC (relating to freedom of movement for workers), as interpreted by the ECJ in numerous judgments. It means, in concrete terms, that nationals from one Member State who want to work in another Member State need a residence permit, for which they must produce proof of engagement from an employer. Similarly, family members, whether from a Member State or a third country, must produce proof of their relationship with the worker. it was expanded with the rights to good administration and access to documents. The enumeration of these lists of rights in the EC Treaty, as amended, and in the EU Charter may seem rather symbolic, many of the rights mentioned being already specified in other treaty provisions. However, the fact should not be overlooked that the rights enumerated in Articles 18 to 21 EC are granted to all citizens, that is, they are unconnected with the exercise of any economic activity. That obviously holds true for the political rights, but it is also becoming increasingly true, as we will see below, for the general right of citizens, established in Article 18 EC, to move and reside freely within the territory of the Member States (Pettit, 1997). Among the rights conferred by other treaty provisions are the rights that workers from other Member States, and by extension members of their family (so-called â€Å"dependents†), enjoy in the Member State where they work. 188 These rights remain connected, however, to the status of â€Å"worker† in the sense of Article 39 (1) EC (relating to freedom of movement for workers), as interpreted by the ECJ in numerous judgments. It means, in concrete terms, that nationals from one Member State who want to work in another Member State need a residence permit, for which they must produce proof of engagement from an employer. Similarly, family members, whether from a Member State or a third country, must produce proof of their relationship with the worker. [1] A financial burden on the host Member State, the students right of residence was directly based on Article 18 EC, with the effect that he was entitled in Belgium to financial assistance available to Belgians. In fact, not only EU citizens but also third-country nationals enjoy social rights under certain conditions, principally when they are family members of migrant workers, or migrant workers from countries with which the EU has special agreements. In this context, the Mary Carpenter case deserves to be mentioned: it concerned the right, under EU law, of the non-EU spouse of a U.K. national to remain with him in the United Kingdom, despite her having violated immigration rules. The ECJ ruled in that case that, since the deportation of his spouse (who cared for children from his previous marriage) could adversely affect the husband in the exercise of his (EC) right to provide services in other Member States, the situation fell within the scope of EC law. Furthermore, the Court held that although a Member State may limit the right to provide services on grounds of public policy or public security (as mentioned in Article 46 referring to Article 55 EC), the Member State concerned is bound to observe the human rights requirements embodied in EC law, including respect for the right of family life, as laid down in Article 8 ECHR. Citing the Boultif judgment of the Court of Human Rights, the ECJ held that the U.K. would be violating the right to respect for family life if it expelled Mrs. Carpenter without a more significant public policy reason than violation of immigration laws. The ECJs case law deriving social rights for Union citizens from the free movement and residency right embodied in Article 18 EC raises the delicate issue of how far the ECJ can go in imposing financial burdens on Member State social security systems in the name of solidarity between Union citizens. The issue is underlying many recent judgments, but is most apparent in Baumbast. In that case, the ECJ ruled that Article 18 (1) EC is sufficiently clear and precise to be directly applicable (and directly effective), and this despite the fact, as pointed out previously, that the article submits the free movement and resident right â€Å"to the limitations and conditions contained† in the treaty and in secondary legislation. The question at issue was whether the U.K. immigration authorities could reject Mr. Baumbasts application for renewal of his residence permit on the grounds that he and his family were not insured for emergency treatment in the U.K., where the family lived (although they were covered by comprehensive medical insurance in Germany, of which Mr. Baumbast was a national). Such a residence permit is needed under the three EC directives granting rights of residence to categories of persons other than workers. These directives provide that rights of residence are subject to two conditions: first, the applicant must possess sufficient resources, and, second, he or she must have comprehensive medical insurance for all risks. It was clear, as the court observed that Mr. Baumbast had sufficient resources, but it was equally clear that he had no health insurance for emergency treatment within the U.K (Dougan Spaventa, 2003). In its judgment, the ECJ ruled that the refusal of the British authorities was unfounded. It recognized that the requirements in the directives were permissible, being based on the idea that exercise of the Union citizens right of residency can be subordinated to the legitimate financial interests of the Member State, including the fact that foreign nationals should not become an â€Å"unreasonable burden† on the public finances of the host state. Nevertheless, those limitations and conditions, laid down in secondary Community legislation, must be applied in compliance with general principles of Community law, and in particular with the principle of proportionality. The Court then found that to deny Mr. Baumbast residence solely on the grounds that he lacked medical insurance for emergency treatment within the United Kingdom would be a disproportionate interference with the exercise of his residency right under Article 18 (1) EC. Conclusion The difficulty with the ECJs case law in this case, but also in other â€Å"social rights† cases, is that the Court, and the EU, â€Å"cannot simply grant full rights of residency to all its citizens, because it cannot foot the consequent welfare bill, especially in respect of economically inactive individuals. The aspiration towards a supranational form of social citizenship, which many see embodied in Article 18, must therefore remain sensitive to domestic conceptions of belonging to (and being excluded from) the welfare society.† Apart from this basic question, many other issues of a more specifically legal nature arise, such as which general principles other than proportionality will be permitted to qualify restrictions imposed by secondary Community legislation. The question is most acute with regard to economically inactive and financially dependent persons: What are the benefits of Union citizenship for them? Should they not be able to derive residency rights from fundamental rights provisions, such as respect for private and family life and for human dignity? Should these rights not have an impact upon the ability of Member States to expel individuals who would otherwise be considered an unreasonable burden upon the public purse? A straight answer to that question would be to grant Union citizens who have been lawfully resident in another Member State, for example, at least five consecutive years â€Å"permanent resident† status regardless of their economic or financial status, as is proposed by the Commission in a draft general directive which, if adopted, would replace much of the existing secondary legislation. References Bright; Christopher. Business Law in the European Economic Area. Oxford University, 1994 Case C-413/99, Baumbast and R v. Secretary of State for the Home Department, [2002] ECR I-7091. Case C-60/00, Mary Carpenter v. Secretary of State for the Home Department, [2002] ECR I-6279. Dougan, Michael and Spaventa, Eleanor; â€Å"Educating Rudy and the (Non-) English Patient: A Double-bill on Residency Rights under Article 18 EC, † 28 ELRev., 2003, 699–712. Forder, Caroline; â€Å"Editorial: Common Minimum European Standards in Immigration Matters, † 9 MJ, 2002, 221–29. Groenendijk, Kees and Guild, Elspeth; â€Å"Converging Criteria: Creating an Area of Security of Residence for Europes Third Country Nationals, † 3 EJML, 2001, 37–59, at 52. Goyder; D. G. EC Competition Law. Oxford University Press, 1998 Jarvis; Malcolm A. The Application of EC Law by National Courts: The Free Movement of Goods. Oxford University, 1998 Leibfried, Stephan; Pierson; Paul; European Social Policy: Between Fragmentation and Integration. Brookings Institution, 1995 Pettit, P. Republicanism: A Theory of Freedom and Government (Oxford: Clarendon Press, 1997). Peers, Steve; â€Å"Implementing Equality? The Directive On Long-Term Third-Country Nationals, † 29 ELRev., 2004, 437–60. Proposal for a European Parliament and Council Directive on the Right of Citizens of the Union and their Family Members to Move and Reside Freely within the Territory of the Member States: COM (2001) 257 final. Reich, Norbert and Harbacevica, Solvita; â€Å"Citizenship and Family on Trial: A Fairly Optimistic Overview of Recent Court Practice with Regard to Free Movement of Persons, † 40 CMLRev., 2003, 615–38. [1] The most important of these measures are: Council Directive 68/360, containing formal requirements for workers and their family members, and Council Regulation 1612/68, concerning the substantive rights and social advantages that workers and their family members enjoy. Further directives relating to rights of residence granted to categories of persons other than genuine workers are: Directive 90/366, replaced later by Directive 93/96, covering students exercising the right of vocational training; Directive 90/365, dealing with persons who have ceased to work; and catch-all Directive 90/364, governing all those persons who did not already enjoy a right of residence under Community law. These three residency directives have in common that the persons involved must have adequate resources not to become a financial burden on the social assistance schemes of the host Member State and must be covered by sickness insurance. For references, see Craig and de Bà ºrca, n. 36 above, 756. Th e scope of these directives was reconsidered by the ECJ in its Grzelczyk and Baumbast judgments mentioned later in the text.

The drug metabolism

The drug metabolism Introduction: If an exogenous microorganism enters the human body, this invokes the immune system to produce antibodies to come into contact with the foreign potentially pathogenic species and lead to its destruction. Although when drug molecules enter the human body this does not result in the synthesis of antibodies, due to their relatively small molecular weight. This is why the endogenous metabolism of drugs is vital in ensuring no or the minimum toxicity from a very broad spectrum of xenobiotics i.e. molecules/compounds which are found in a given organism, but are not synthesized naturally by it and or normally found within it. We can define drug metabolism as the enzymatically catalysed conversion of exogenous drug molecules into generally less active metabolites, which have a faster rate of clearance from the body. (While this is true for the majority of metabolites it is important to acknowledge that some metabolites actually are of higher toxicity than their precursors.) This occurs throu ghout nearly every organ (excluding ectodermal tissue) in the human body, but specifically the gastro-intestinal tract, lungs, kidneys and most importantly (and abundantly) the liver. While drug metabolism is essential in preventing a specific toxicity being produced from the accumulation of a drug(s), there are drawbacks that need to be addressed; a given drug may be a xenobiotic, but it is taken (or administered) in order to produce some degree of a therapeutic effect for its specifically targeted disease/pathology. Thus drug metabolism can inhibit the therapeutic benefit of a given molecule that ideally needs to be retained in a particular tissue of the body for a set period of time, to bring about a therapeutic effect. This is mainly due to the fact that a large number of drug molecules do mimic the structure of endogenous molecules close enough for the corresponding specific enzymes to target them as well as nonspecific enzymes which only identify certain molecular groups as opposed to the entire pharmacophore of a given drug. This unexpected drug metabolism could result in an undesired decrease in the bioavailability of a drug which would lead to increased d oses or dosage frequencies; this would cause a decrease in patient compliance which in the current medicinal environment is vital. Absorption and clearance: In the case of drug absorption into the desired tissues of the body generally a lipophilic character is required. This is because regardless of the site of drug uptake, it must pass through the cell membranes of targeted cells. These cell membranes are lipophilic in nature as they consist of a phospholipid bilayer. The inside of this bilayer is made up of hydrocarbon tails which are straight chain hydrocarbons which interact with each other via Van der Waal interactions and London forces. Thus drug molecules are designed to have sufficient lipophilic character that they can form these interactions with the lipid bilayers and pass into cells. Unfortunately this means that they are of limited hydrophilicity and either do not go into dissolution in an aqueous environment at all or do so at a very slow rate. As previously mentioned as this is unacceptable due to the accumulation of a given drug that would occur and produce toxicity, the drug must undergo a series of transformations that serve to increase the hydrophilic nature of the drug molecules. This predominately occurs in liver cells (hepatocytes) in processes known as phase I and phase II metabolism. Phase I and Phase II: Phase I metabolism is constituted of oxidative, reductive and hydrolytic reactions. These serve to produce primary metabolites that are susceptible to other reactions, which consist of the following conjugations; glucuronic acid, sulphate, amino acid, glutathione, water, acetyl, fatty acid and methyl. These occur via the corresponding conjugating agents and are known as phase II reactions. They aim to produce secondary metabolites that are far more hydrophilic nature than their precursor drug counterparts. This is with the addition of e.g. amine, carboxylic acid, hydroxyl groups as well as others, simply to increase the number of very electronegative atoms (with lone pairs of electrons) in a given species. Thus these metabolites can from a greater number of hydrogen bonds with the aqueous medium of the nephronal filtrate of the kidneys and be excreted at a faster rate via the passing of urine. The main constituent of phase I transformations are oxidative reactions, as they activate the selected species in generally one of two ways; hydroxylation and epoxidation. We can define oxidation as the gain of oxygen in a molecule or more precisely the loss of at least one electron from a species reacting with molecular oxygen. This is true for the two general mechanisms mentioned above as adding either a hydroxyl group or an epoxide ring to a molecule increases the number of oxygen atoms that the molecule contains. Firstly this increases the ability of the newly formed metabolite to act as a nucleophile due to the lone pair of electrons available for covalent bond formation (from the oxygen atom added to the molecule). Secondly it increases the chances of attack by an electrophilic species, because of the high electron density of the lone pair of electrons on the oxygen atom. Oxidation Properties and mechanisms of the Cytochrome P450 isoenzyme superfamily: The majority of these oxidative metabolic reactions are carried out by a superfamily of enzymes known as cytochrome P450, this can be displayed as: RH + O2 +NAD(P)H + H+ ? ROH + H2O + NAD(P)+ [1] The P450 enzymes catalyse the biodegradation of other exogenous species that are not drugs such as; organic solvents, ethanol (or consumed alcohol), anaesthetics, pesticides and carcinogens [1]; While endogenous molecules such as organic acids, steroids and prostaglandins are also biodegraded [1]. These enzymes are intracellular hemoproteins that function as external monooxygenases (mixed function oxidases) enzymes that serve to incorporate a single atom of molecular oxygen into a lipophilic xenobiotic substrate (i.e. a drug molecule), with the concomitant reduction of the other atom to water [1]. While internal monooxygenases take two reductive equivalents from the substrate in order to reduce one atom of molecular oxygen to water, this is normally done with an external reductant for external monooxygenases [1]. In eukaryotic cells the P450 enzymes consist of around half a thousand amino acid that compose their quaternary structure, these hemoproteins are membrane bound and have a heme prosthetic group at their centres. It is thought that the reason the enzymes can be bound to the cell membranes is the N-terminus of the enzymes tertiary structure has numerous hydrophobic amino acids (i.e. ones which contain aromatic/cyclic groups and have few very electronegative atoms such as oxygen and sulphur) that can interact with the lipid bilayer of the cells. Most hemoproteins in mammalian cells have nitrogen atom from the histidine residues imidazole group to form a ligand with the iron-heme prosthetic group. While for P450 enzymes this ligand is formed between the prosthetic group and the thiol group of a cysteine residue which is located near the C-terminus of the protein. This ligand activates the porphyrin ring (four conjugated pyrrole rings) to nucleophilic substitution by an oxygen atom. This is because the thiol group has an electron inductive effect due to its high electronegativity and so makes the carbon atom it is directly bonded to very electropositive and thus of greater electrophilicity/susceptibility of nucleophilic attack by the lone pair of electrons from the oxygen atom, so allowing oxidation to take place. The general process of the catalytic oxidative cycle of the cytochrome P450 enzyme superfamily: The substrate binds to a specific P450 enzyme and is followed by the first electron of the coenzyme NADPH via the electron transport chain. This is then followed by the binding of an oxygen atom that accepts the second electron from the coenzyme to produce a ferric peroxy anion [1]. The anion forms a ferric hydroperoxy complex via protonation, which in turn is heterolytically cleaved to form a Fe(V)=O species [1]. The newly formed highly electrophilic iron-oxo intermediate then attacks the substrate to form a hydroxylated metabolite. This product disassociates to allow another substrate to bind and the oxidation cycle to continue [1]. Schematic organisation of different cytochrome P450 systems. Upper row, left: bacterial system, right: mitochondrial system. Lower row, left: microsomal system, right: self-sufficient CYP102 (P450-BM3).[1] Aromatic hydroxylation: This leads on to the first major constituent of oxidative reactions; aromatic hydroxylation. This is simply the addition of at least one hydroxyl group to a given substrate although depending on the chemical environment that the product is formed in (e.g. pH) the hydrogen atom may be lost from the hydroxyl group. Aromatic compounds are first metabolized to the corresponding arene oxides; this is by electrophilic addition of the aromatic ring (of the previously mentioned iron-oxo intermediate) to produce either a carbocation species. This carbocation would be formed via the movement of an electron to the Fe(IV) species, giving a Fe(III) species bound to a the mentioned carbocation; or by formation of a radical which serves as a tetrahedral intermediate. The produced arene oxides then take on further transformations, which involve removal of the epoxide group that was added and introduction of a hydroxyl group and potentially another nucleophilic substitute. The simplest transformation is simply intramolecular rearrangement to for a para-arenol. Also hydration can take place in the presence of water and using the enzyme epoxide hydrolase. This causes opening of the epoxide ring and formation of a trans-3,4 arenediol. These primary metabolites can also undergo attack by large macromolecules which serve as nucleophiles. This is because the oxygen in the epoxide ring serves to make both the meta and para carbon positions electropositive and electrophilic in nature. Although any nucleophilic substitution that does go on to occur is at the para position, due to greater resonance stability of the formed secondary metabolite. Another example of aromatic hydroxylation would be the metabolism of isoliquiritigenin. It is a chalcone found in licorice roots and other plants [3] which has shown potent antitumor, phytoestrogenic activity and antioxidant properties. [3] Schematics for its metabolism can be shown below. [3] The metabolism of aromatic compounds that get hydroxylated can be slowed by using para-substituted aromatic compounds with either chlorine or a fluorine atom in the para position. While electron withdrawing groups deactivate the ring towards electrophilic substitution and activate it towards nucleophilic substitution; electron donating groups activate the ring towards electrophilic substitution and deactivate it towards nucleophilic substitution. While most ring deactivators go in the meta position, halogens direct ortho-para, i.e. the same as ring activators. This is because the halogens, especially fluorine and chlorine are very electronegative and thus have an electron inductive effect and decrease the electron density of the ring. This inductivity is far greater than the resonance stability that the halogen can give the ring thus deactivating it. Thus the addition of these halogen atoms decreases the nucleophilic nature of the ring and decreases the rate of metabolism. This can b e shown with the metabolism of the drug Diclofenac (shown below [4]) which is an anti-inflammatory drug as it is has a half-life of around one hour. While its derivative fenclofenac which has a para-substituted chlorine atom has a half-life twenty times longer. Alkene epoxidation: Epoxidation of alkenes occurs readily, because they are more volatile than the ? bonds of aromatic compounds, this simply involves the addition of an epoxide ring to a molecule in order for it to then undergo further transformations. For example the drug Coumarin has been used clinically at high dosages in humans in the treatment of high-protein lymphedemas (Jamal and Casley-Smith, 1989) and as an antineoplastic agent in the treatment of renal cell carcinoma (Marshall et al., 1994) and malignant melanoma (Marshall et al., 1989). [5] It and its 3/7-hydroxy isomers undergo epoxidation and then either glutathione conjugation or non-enzymatic intramolecular rearrangement [5] to secondary metabolites. This is shown schematically below. [5] It is also vitally important that environmental carcinogens are broken down via drug metabolism, in particular by the P450 enzymes. For example acrylonitrile (AN2) is widely used in the production of acrylic and modacrylic fibres, plastics, rubbers, resins, and as a chemical intermediate in the synthesis of many other industrial products (IARC,1999). Early epidemiological studies have suggested that AN may increase the incidence of lung, colon, and stomach cancers among exposed workers (Thiess and Fleig, 1978; Blair et al., 1998).[6] As a result P450 epoxidation is vital for preventing carcinogenic action of AN. While the metabolic basis of the acute toxicity of AN has not been fully elucidated, it is generally attributed to its metabolism to CEO (cyanoethylene oxide) and cyanide, and glutathione depletion. The primary target of acute toxicity of AN is the central nervous system due, at least partially, to the liberation of cyanide (Ahmed and Patel, 1981; Benz et al., 1997). [6] The below diagram illustrates how AN is metabolised by the P450 enzymes, specifically the CYP2E1 isoform.[6] Alcohol and aldehyde metabolism: Alcohols and aldehydes can be metabolized by cytochrome P450 enzymes to aldehydes and carboxylic acids respectively, but the majority of these transformations are catalysed by alcohol dehydrogenase and aldehyde dehydrogenase. These enzymes are predominantly in the liver and require the coenzyme NAD+ or NADP+. General equations for these reactions are shown below. [Alcohol Dehydrogenase]Ez + RCH2OH + NAD + RCHO + NADH + H+ [Aldehyde Dehydrogenase]Ez + RCHO + NAD+ + H2O RCOOH + NADH + H+ Reduction: Cytochrome P450 enzymes are used along with reductases to metabolise drugs that have a carbon atom that is able to be reduced such as a carbonyl or an unsaturated carbon, a nitro group or a compound with an azo group. In addition upon reaction usually a specific stereoisomer is formed. The structure of the rest of the compounds often attribute to which stereoisomer is formed. Some stereoisomers can prove to be toxic. Carbonyl compounds: Carbonyl compounds are reduced by cytochrome P450 into alcohols and are NADP or NADPH dependent. The enzymes involved in the reduction of carbonyls are classified based upon their gene sequence, 3-D structure and cofactor dependence into superfamilies of; medium-chain dehydrogenases/reductases, aldo-keto reductases, short-chain dehydrogenases/reductases which include carbonyl reductases. The majority of these enzymes are present in the cytosol however there are some that are found in the microsomes and mitochondria. Short-chain dehydrogenases/reductases (SDRs) and aldo-keto reductases (AKR) are the most common enzymes used in drug metabolism. These enzymes also exhibit high specificity for the drugs that they reduce. Saturated ketones reduced to alcohols whilst in an unsaturated ketone both the ketone group and the double bonds are both reduced. Steroidal drugs undergo oxidoreduction of the hydroxy/keto group at C17[7]. This makes the compound more water soluble and hence easier to be excreted. Some metabolising enzymes behave differently and undergo different types of reactions when in different cells. An example is carbonyl reductases within tumour cells and normal cells. These have become a target of new drugs such as oracin in the treatment of breast cancer [9]. The enzymes within the cancer cells metabolise oracin and doxorubin more effectively than in normal cells hence reducing the efficacy of the cytostatic effect of the drugs. Some carbonyl compounds however do not undergo reduction via the cytochrome P450 pathway but are rather reduced by other pathways including the aldo-keto reductases (AKR). An example is a drug containing a 1,3-diketone derivative S-1360 which upon reduction produces a key metabolite HP1 which constitutes a major clearance pathway[9]. Nitrogen compounds: The reduction of nitrogen containing compounds are reduced to amines in order to aid excretion as amines are more water soluble than their nitro groups. Azo compounds on the other hand may be metabolised within the body to produce the active drug as opposed to the precursor which may be formulated to get pass the first pass effect or the hydrophilic barrier in order to enter their target cells. The azo group provides 2 compounds with amine groups which can be further metabolised like any other amine. Both of these functional groups are both reduced by cytochrome P450 enzymes and are NADPH dependent. Hydrolysis: This is part of the Phase I metabolism pathway. The metabolites produced are all susceptible to Phase II conjugation and thus being excreted after the conjugation. The functional groups of the drugs that are metabolised by hydrolysis include esters and amides, which produce carboxylic acids, alcohols and amines. Esters are hydrolysed quicker than amides in vivo. Unlike oxidation and reduction the reactions are typically not carried out by the cytochrome P450 system. The most significant enzymes involved in the hydrolysis of the esters and amides are carboxylesterases and arylesterases, cholinesterases and serine endopeptidases. The active site of the enzymes involved may be stereospecific as to which enantiomer of the drug is metabolised and in addition which enantiomer of the drug is generated. Some of these products are toxic and dangerous to the body. Amino acid reactions Several phase I reactions produce a carboxylic acid metabolite. Xenobiotic carboxylic acids can be metabolised before elimination by amino acid conjugation. Glycine; the most common conjugating amino acid forms ionic conjugates that are water soluble with aromatic, arylaliphatic and heterocyclic carboxylic acids. In these reactions, first the xenobiotic carboxylic acid is activated by ATP to form the AMP ester by the enzyme acyl synthetase. Then the AMP ester is converted to a Coenzyme-A thioester. Next, an amide or peptide bond is formed between the thioester and the amino group of glycine. The latter reaction is mediated by the enzyme acyl transferase. These reactions are shown in figure 1. The amino acid conjugate produced is ionic and therefore water soluble, hence it is easily eliminated in the urine and bile. (1) Glutathione conjugation Glutathione is a protective compound in the body that removes potentially toxic electrophilic compounds and xenobiotics. Drugs are metabolised by phase I reactions to form strong elecrophiles that can react with glutathione to form conjugates that are not toxic. This phase II reaction differs from others since electrophiles are subject to conjugations rather than nucleophiles. The nucleophilic thiol group on the glutathione compound (figure 2) attacks elecrophiles (electrophilic carbons with leaving groups). Compounds that can be conjugated to give thioether conjugates of glutathione: Epoxides Haloalkanes Nitroalkanes Alkenes Aromatic halo- and nitro- compounds Glutathione-S-transferases (GST) are enzymes which catalyse the reactions above. There are thirteen different human GST subunits which have been identified and they belong to five different classes. They are located in the cytosol of the liver, kidney and gut. The enzyme GST is thought to increase the ionisation of the thiol group of glutathione, leading to an increase in its nucleophilicity towards electrophiles. (1)(2) Once formed, GSH conjugates may be excreted directly or more often they are further metabolised to N-acetylcysteine conjugates which can then be excreted via phase III metabolism. Phase III Metabolism further modification and excretion Before being excreted in the urine, most xenobiotics are made less toxic and more water soluble as polarity increases by metabolising enzymes in phase II reactions. In phase III metabolism water soluble compounds are excreted in the urine. However, some drug compounds are not metabolised and therefore are not excreted. These non-metabolised compounds are readily reabsorbed from the urine through the renal tubular membranes and into the plasma to be recirculated. (3) Some xenobiotic conjugates from phase II reactions are further metabolised during phase III metabolism reactions. Glutathione-S conjugates may be metabolised further by hydrolysis of the glutathione conjugate (GSR) at the y-glutamyl bond of the glutamate residues by y -glutamyl transferase (y -GT) followed by hydrolysis of glycine residues resulting in a cysteine conjugate containing a free amino group of the cysteine residue. This then undergoes N-acetylation to form mercapturic acid. The final products; mercapturic acids are S-derivatives of N-acetylcysteine synthesised from glutathione (figure 4). (1)(2) First-pass Metabolism The metabolism of many drugs is dependent on the route of administation therefore orally administered drugs are subject to first pass metabolism and consequently their bioavailablity is reduced. This occurs as a result of the orally administered drugs entering the systemic circulation via the hepatic portal vein, so the drug is exposed to the intestinal wall and the liver, which is thought to be the main site of first-pass metabolism of orally administered drugs. Other possible sites are the gastrointestinal tract, blood, vascular endothelium and lungs. First-pass Metabolism in the Liver During first-pass metabolism, the cytochrome P450 enzymes family represent the most significant of the hepatic enzymes. It has been estimated that the endoplasmic reticulum of the liver contains approximately 25 000 nmol of cytochrome P450. Although there are several human P450 subfamilies and multiple individual isozymes within subfamilies, only five P450 enzymes are shown to be significant for the process of first-pass metabolism: CYP1A2 CYP2C9 CYP2C19 CYP2D6 CYP3A4 Cytochrome P450 drug substrates are commonly highly extracted during first-pass metabolism. Examples of these drugs are; morphine, verapamil, propranolol, midazolam, lidocaine. Drugs that are highly extracted such as lidocaine have a low bioavailability when taken orally therefore they are not administered orally. CYP3A4 is the most commonly active isozyme against P450 drug substrates. This is possibly due to the enzymes abundance and broad substrate specificity. Highly extracted substrates for conjugative, reductive or non-P450 oxidative enzymes are less common. These include labetalol, morphine, terbutaline, isoproterenol and pentoxifylline. The gut is also an important organ involved in pre-systemic metabolism. Metabolism here for drugs with high first-pass metabolism leads to a reduced bioavailability. Some metabolizing enzymes such as CYP3A4 is found at a higher level in enterocytes than in the liver. Recent findings state that gut wall metabolism is the major cause of low bioavailability of certain drugs. Intestinal First-pass Metabolism Various drug metabolizing enzymes found in the liver are also found within the epithelium of the gastrointestinal tract. These include cytochromes P450, glucuronosyl transferases, sulfotransferases, N-acetyl transferase, glutathione S-transferases, esterases, epoxide hydrolase and alcohol dehydrogenase. The small intestine contains high amounts of three cytochrome P450 enzymes; CYP3A, CYP2D6 and CYP2C. Unlike the liver which has a relatively uniform distribution of P450enzymes, the distribution of P450 enzymes is not uniform along the small intestine and villi. Proximal mucosal P450 content is normally higher than distal mucosa P450 content. Therefore it has been established that protein level and catalytic activity of drug-metabolizing enzymes in the small intestine are generally lower than those in the liver. This has been demonstrated by comparison of cytochrome P450 enzymes in the liver and the small intestine. The extent of first-pass metabolism can result from interindividual variability: Genetic variation Induction or inhibition of metabolic enzymes Food increases liver blood flow. This can increase the bioavailablity of some drugs by increasing the amount of drug presented to the liver to an amount that is above the threshold for complete hepatic extraction Drugs that increase liver blood flow (similar effects to food) and drugs that reduce liver blood flow Non- linear first pass kinetics, i.e. dose Liver disease increases the bioavailability of some drugs with extensive first-pass metabolism (4) To avoid first pass metabolism a drug can be administered sublingual and buccal routes. These routes lead to drugs being absorbed by the oral mucosa. During sublingual administration the drug is put under the tongue where it dissolves in salivary secretions. An example of a sublingual drug is nitroglycerine. During buccal administration the drug is positioned between the teeth and the mucous membrane of the cheek. Both of these routes avoid destruction by the GI fluids and first pass effect of the liver. Drugs may also be administered via other routes to avoid first-pass metabolism, for example; rectal, inhalation, transdermal, intravenous. (5) Prodrugs Many drugs require metabolic activation in order to exert their pharmacological action; these are described as pro-drugs. There are two types; type I and type II which has subtypes A and B dependent on the site of activation. Type I prodrugs are converted intracellularly at the target cells (A) or at tissues that usually metabolise compounds (B). An example of a type IA prodrug is Zidovudine and type IB prodrug is captopril. Metabolic activation of type I prodrugs is usually linked to phase I metabolic enzymes. Type II prodrugs are converted extracellularly in GI fluids (A) or in the systemic circulation (B). An example of a type IIA prodrug is sulfasalazine and type IIB prodrug is fosphenytoin. Type II prodrugs are very popular as they are involved in overcoming bioavailability problems, which are commonly experienced with many drugs, by improving permeability and reducing the first pass effect. (6) Type I Prodrugs are used to target a drug to its specific site of action; an example of this is the drug used in Parkinsons disease levodopa; the inactive form of the drug which is metabolised in the neurone by the enzyme dopa decarboxylase to the active form; dopamine. Dopamine does not cross the blood-brain barrier so it is given as the levodopa precursor which is lipophilic so it can cross the barrier and then metabolized in vivo to dopamine. (7) Another example of the use of prodrugs is the pharmacological activation of a type II prodrug Azathioprine to mercaptopurine which is a chemotherapeutic agent used in the treatment of leukaemia. When mercaptopurine is administered, its clinical usefulness is restricted because of its rapid biotransformation by xanthine oxidase to an inactive metabolite 6-thiouric acid. Therefore larger doses have to be given as it has a low bioavailability, this leads to toxicity. By administering mercaptopurine as its cysteine conjugate, the limitations can be overcome. This ionic form of the pro-drug conjugate is selectively taken up by the renal organic anion transport system. The kidney B-lyase enzyme system then cleaves the prodrug conjugate to give the active mercaptopurine in the kidney (figure 5). (8)(9) To conclude, prodrugs can be metabolised in different ways to form the active drug. They can be used to target specific sites, improve absorption and improve oral delivery of poorly water-soluble drugs. They can also be used to avoid first pass metabolism in drugs with high first pass extraction and reduce toxicity. (6) Factors affecting metabolism There are several factors that can affect drug metabolism. Age, sex, inducers and inhibitors are some of which can effect drug metabolism which are mentioned below. How does age affect drug metabolism: There are many physiological changes that occur with ageing. The changes have the potential to affect both drug disposition and metabolism. Drug metabolism is mainly functioned by the liver, its size, blood perfusion and synthetic capacity for proteins which all determine the rate of hepatic drug elimination[5]. Paediatric population Phase one and phase two metabolic pathways may not be active at birth due to maturational changes. The paediatric population and elderly population have differences in their capacity to metabolise a drug which can therefore produce a lower or higher plasma concentration of active substances compared with adults depending on the enzyme system used. There are examples of metabolites produced by therapeutic agents in children that are not usually seen in adults. The metabolites produced maybe the reason for some of the efficacy and or toxicity visible with drug administration in children. An example is: caffeine production in a neonate receiving Theophylline. Other therapeutic agents which show changes in metabolite production in children are; Valproic acid, paracetamol, Chloramphenicol, Cimetidine Salicylamide. In most cases the differences that occur between children and adults are in the ratios of the metabolites relative to the parent drug rather than in new metabolites individual to the paediatric population with some exceptions. The paediatric population shows the same set of enzymes as the adult population. (1) In general age related changes in drug metabolism have been shown to occur due to a consequence of diminished enzyme activities within the elderly human liver due to the size of the liver decreasing and hepatic blood flow decreasing. With age the liver blood flow is generally reduced by about 20-30% and there is a decrease in liver size by about (17-36%). Currently there is no clear pattern; however there are two general trends that influence the rate of metabolism. One trend is that drugs that are undergoing hepatic microsomal oxidation are more likely to be metabolised slowly in the elderly and those which are conjugated are not likely to be influence by the age factor. Secondly, drugs that have high hepatic clearance, extraction ratios example-Chlormethiazole, and Labetalol and undergo extensive first pass metabolism whilst oral absorption may show a large increase in bioavailability in the elderly. Elderly population In general in the elderly population hepatic blood flow decreases up to 40% and there can be a considerable reduction in the amount of drug reaching the liver per unit. Studies have shown that the effect of ageing on liver enzymes with particular drug