Corporate Social Essay Example | Topics and Well Written Essays - 1500 words

Corporate Social - Essay Example This paper examines the significance of CSR system for the associations and the difficulties looked by associations when they actualize such a methodology. The corporate social duty system is significant for the associations as this technique mulls over the adequacy of the association by the customers of the specific locale. This procedure needs to mull over the corporate administration factors; this technique guarantees that the association is directing its tasks in a capable manners and will be responsible for all its business exercises that are affecting the earth (Brooks, Williams, and Thomas, 2004). Actualizing a corporate social duty technique in the association is a key issue. This is so in light of the fact that this system permits associations to direct their business by keeping up solid and cheerful relationship with their partners and the network (Hemingway and Maclagan, 2004). The clients are significant for the achievement of the association, when clients have at the top of the priority list that the association is a socially dependable association, the notoriety of the association further improves thus does the client base. This positive picture ends up being helpful for the association in the long haul. In the event that associations don't consider the network and their business activities hurt the network then there has a high potential for success of business disappointment in that network. Clients may get the message that this specific association isn't worried about the government assistance and prosperity of the individuals (Levy, 2007). Any negative message transmitted to the customers by any business movement will make the association face substantial results. In this way, keeping in see the investors and the network is significant for organisation’s achievement. The investors or the association, the significant clients and the workforce of the association, every one of these components have desires with the business and

Water Pollution in Textile Industry Free Essays

Decrease In the con. [amount of synthetic substances utilized in this way lessening their hurtful impacts. Decrease of waste fixation by recuperation and reuse. We will compose a custom article test on Water Pollution in Textile Industry or on the other hand any comparable subject just for you Request Now Decrease of waste fixation by synthetic replacement. Decrease of waste focus by process adjustment. Isolation of Fenton of each procedure. Conceiving reasonable treatment for extreme removal, to meet the prerequisites. To investigate the financial aspects identified with reuse of treated Fenton. Decrease In squander water volume Reducing the quantity of washing and utilization of boiling water in washings utilization of counter ebb and flow washing utilization of standing shower in coloring Use of low Liquor Ratio frameworks Good house keeping and anticipation of spillages and spillages (A decrease of 20-40 volume of wastewater produced Is conceivable) Reduction In con. /measure of synthetic substances Optimum use is vital, which isn't constantly conceivable in material handling industry Textile preparing includes heterogeneous cooperations between fiber material †strong and synthetic substances †fluid, arrangements or emulsions. Fundamental activities engaged with Textile Processing : Maximum infiltration of synthetic concoctions into fiber material to accomplish wanted Interactions. Exhaustive evacuation of unused/unfixed synthetic compounds and Impurities from the material. On account of the heterogeneity of Interaction, just Limited assimilation f different sorts of synthetic concoctions and coolants utilized for substance preparing onto the material fiber materials is conceivable. Decrease of waste con. By recuperation and reuse of Recovery of manufactured estimating specialists from wanting shower and their reuse. Receptive colors have extremely low BODY) Multifunctional responsive colors for better obsession less unfixed Use of non-ionic decorate greasy alcohols and anionic polymerases instead of alkyl phenol decorates CEO-accommodating stabilizers, sequestrates Use of mineral corrosive in wanting Use of compounds in different procedures Substitution of sodium sulfide for sulfur colors Disperse-hydrocarbon transporters No or less lamp oil in Pigment Printing Partial or complete substitution of printing gums by appropriate emulsions Formaldehyde free cationic color fixing operator, DEEMED, low formaldehyde Low salt colors Decrease of waste con. By process alteration Use of Foam innovation Use of move paper printing Combined procedures Automatic administering Segregation of channel Many multiple times it is advantageous to isolate the waste water of a specific material wet procedure for proficient reuse/recuperation of synthetic concoctions or colors. This prompts economy of the procedure. Anyway it is most extreme important to have adequate grouping of the concoction/color in the waste water that can be monetarily recuperated and put to reuse. On the off chance that the focus is excessively low or in the event that the compound is modest, at that point this strategy s ineffectual. Conceiving reasonable treatment for extreme removal Depends on method of release of gushing. Harmony between the capital expense and running expense of treatment. In the event that removal is into open sewers, fundamental treatment (screening, coarseness expulsion and adjustment) followed distinctly by essential treatment with substance coagulation, flocculation and sedimentation will be vital. In the event that removal is legitimately to stream, at that point essential and auxiliary treatment is fundamental. On the off chance that removal is on the horticulture land, essential treatment followed by gypsum treatment for decrease of sodium will be important. The most effective method to refer to Water Pollution in Textile Industry, Essays

Americas Debt and Budget Deficit

Americas Debt and Budget Deficit Americas Debt and Budget Deficit Home›Economics Posts›Americas Debt and Budget Deficit Economics PostsIntroductionThe American debt and budget deficit problems have been on the increase for several years now. In 1992, the national debt stood at $4 trillion, which represented a 64% of the annual Gross Domestic Product. Over the next eight years, the debt was managed and reduced to 56% of the budget. However, it has swollen since then. The current American debt as at today stands at 14,350,296,997,143, which is slightly above 100% of the annual Gross Domestic Product. America has an estimated population of 310,677, 986 which means that every citizen in America shares $ 46,190.17 of the public debt. The means that the national debt continues to grow averagely at $ 3.98 billions per day since 2007.It is predicted that the deficit will continue to grow over the next few years with estimates being $50 trillion by 2030. This represents 140% of the Annual Gross Domestic Product. As the debt ratios continue to rise, the creditors will continue demanding higher interests rates to finance the debt. This, in turn, means that the deficit will continue to get larger and larger, which will force the United States to default its payment. In the light of these facts, I hold that Americas debt is growing to be unmanageable and that it is unsustainable.AnalysisCauses of the increase in the American’s debt.To be able to understand what causes the uprising American debt, it is important to understand what the composition of the debt. The national debt is the amount of money the federal government owes to the public and other agencies. The federal deficit can also be used to explain the national debt, where the expenditure of the states exceeds the revenues. The national comprises of all the debts throughout the history of America plus the interests due from such debts. The state owes the Federal Reserve about forty percent of the total debt, while the remaining amount is owe d to individuals, corporations and foreign governments. This situation is deteriorating by day as the crisis facing the world markets today demand more future borrowing; this means that the debt will continue to grow at a greater rate than the economy (Fink High 18).Knowledge and awareness of the national debt and budget deficit is very crucial for various reasons. One, the national debt is very expensive; the cost of borrowing of these funds is very high. Currently America appends over 900 billion each year in interest payment alone. Secondly, the big national debts cripple the development of the economy. The money given by the public as a loan to finance public social programs would have been used in most productive economic activities. Thirdly, increasing debts means that the government is relying heavily on foreign debts in paying its bills. The gives the individual foreign countries like China and Japan leverage in negotiations with America.Such leverage maybe harmful to the s trategic and competitive interests of America.  Fourthly, the over-reliance on public debt sends signals to market that America has become a risky borrower. This way, the buyers of the bonds will start demanding greater interest rates, to compensate them, in the event that the principal loan is not paid. The other concern facing increased national debt is inflation. For the government to manage the debt, it may cut on expenditure of increase or apply both mechanisms (Konigsberg 94). These policies are not very popular, and the government may result in monetising the debt. The government prints new money to repay the debt. This will result in high levels of inflations, which will affect the value of the dollar.America has had debts since its inception. These debts have continued to accumulate making it so large today. Over the years that American government cut down on taxes and increased its public spending resulting to a more increase in the public debts. The economy and the holde rs of the debt benefit in the short term. The holders enjoy high interest rates to compensate the risks that they will not be paid in the long run. The economy, on the other hand, benefits in the sense that there are funds available for spending. However, this loan and the interest rates on the loans becomes a burden as the government will have to repay the debt eventually (Harrison Dye 101).One of the causes of the increasing debt levels is through budget deficits. This happens when the government exceeds expenses over the revenues it collects from taxes and other revenues over a one year period of time. Each annual deficit is added back to the accumulated debts. When this happens, the government issues debt to cover up the difference. The debt comes in the form of bonds where individuals, corporations and the Federal Reserve buy. The government also loans itself some money through The Social Security Trust Fund. The result of this is increasing the national debt levels.The second cause of increase in the national debt is the increased government expenditure in social programs. This represents the amount of money the government puts aside for public expenditure. This spending is financed either by taxation or by borrowing. CBO projects that public expenditure will double in the next few years to account for over 40% of the GDP. This means that the government will require additional funds. More funds can only be made available through increased taxation or borrowing. This will cripple the American economy and destroy its international competitiveness.The other cause of the increasing debt in America is the Afghan and the Iraq wars. The two wars are estimated to cost the government $ 2.4 to $ 3.5 trillion. The CBO estimates that the war will cost $ 2.4 trillion by the time the war is expected to end by 2017. The democrats on the JEC (Joint Economic Committee) estimate that the war will cost 3.5 billion. This has a very great impact on the national debt. There is no doubt that the war increased the national debt substantially. For the first time, United States cut taxes as it started this war. This meant that the war was fully funded through borrowing.The government has been issuing bonds to be able to finance the war. It has also issued credit cards to China and other foreign buyers to be able to finance the costs of the war. The US debt increased from 6.4 trillion in 2003 to 10 trillion in 2008; a quarter of which is directly attributable to the war. This is exclusive of the future health costs for the disabled veterans of the war, which is likely to add an extra half a trillion to the debt. This is accompanied by very high interest rates; the interest factor comprises of almost 70% of the total amounts borrowed by the government, which continues to increase the national debt immensely. This makes the levels of the debt to be unmanageable and unsustainable. More debts continue to accumulate on every citizen without clear ways on how the debts will be paid. Critics of the war argue that the costs amounting from the war will continue to be passed on the coming generations, who had little to do with the start of the war. However, they have to pay for the debts borrowed today (Bardes 87).The other cause of the ever increasing national debt is the increased expenditure on healthcare, especially Medicaid and Medicare. Medicare is an insurance program for the elderly people aged from 65 years old. Taxpayers cover this insurance, which is usually branded as the health insurance for the poor. Medicare and Medicaid take up to 19% of the federal budget. The government also subsidises the costs of efficient and effective medicines to make them affordable to the poor. The effect of these policies is that they encourage early retirement and fewer saving on medical expenses. In addition, it encourages the over-utilisation of the health facilities. The extra demand resulting from this insurance forces the government to dedicate m ore resources to the health care. This has resulted in increased costs of healthcare. In the face of increased economic hardships, the government seeks foreign funds to take care of the health care. This, in turn, continues to swell the national debt to unmanageable levels.SolutionsTo be able to control the rise in the national debt and budget deficit, the government will have to increase the taxation levels or reduce on public expenditure. As the national debts increases, so does the interest rates payable on these loans. To be able to pay these interest rates, the government and the policy makers will have to increase the amount of taxes charged on people’s incomes. The extra revenues from the taxes would be used to repay the interests rates. However, economists argue that this is not a good way of managing the debts. This is because as more taxes are charged, people get discouraged to work and save resulting in decreased incomes and output. This will make the situation worse. T his is also opposed by the politicians, who fight for the rights of the citizens.To avoid the taxation problem, the government can embark on disinvestment policy, which entails reducing on its public spending, this way; the savings from the reduced funding will be used to pay the debts. This will entail some sacrifices by citizens so that in the future, the debt will be lower. The Keynesian economists hold that this is not a very good for the economy. This is because, when the government reduces spending, so does investments and consumption. This can only be applicable when the economy is near full employment. However, the current expenditure is greater than amounts necessary to maintain and support equitable citizens and an efficient financial system. The government should, therefore, cut on the current expenditure to repay the public debt and avoid it from increasing above the already high limits (Miron 78).The other solution to the national debt problem would be establishing a co nsolidated sinking fund, basically meant to repay the debts. This fund will enable the government to repay the debts instead of issuing new bonds to repay the existing debts. Normally, governments take up debts to repay the due loans. This means that there is a continuous vicious cycle where a debt is repaid using another debt, which means that in, essence, the debt was never paid. The consolidated fund will help to break this vicious cycle.ConclusionThe American debt has been increasing at an alarming rate in the last one decade. There are reasons why the amounts of the debt are going up so fast. First, the ongoing Iraq and Afghan wars are costing the government a lot of money, and thus the government is forced to take more debts to be able to finance the costs. An increase in public spending is another cause for increased debts and budget deficits. The spending is projected to double in the near future. However, these services do not bring in revenues, and so the government have t o seek other sources of finance to finance the debt. The government can raise funds through taxation or through borrowing. Since taxation is not popular with both the politicians and voters, then form of raising funds left is through borrowing, this continues to swell the national debts beyond manageable and sustainable levels (Baumol Blinder 64).The national debts and deficits have very great impacts on the economy of the United States of America. In the short run, the debts results in increased economic growth especially during recessions. Despite this, the long run effects of the debts are quite destructive to the economy. One of the harmful effects is the higher interests to be paid for such loans. This will reduce the amount of money available for the government to invest. Secondly, the American government may fall into the temptation of allowing the dollar value to fall, so it will be cheaper to pay the debts. In this case, foreign investors become reluctant in purchasing the US bonds pushing the interest rates much higher.Quick measures need to be taken to manage the current national debt and budget deficit conditions. However, any abrupt stop borrowing will push the value of the dollar down, push interest rates and inflation up, which would have a more harsh impact on the economy of America and the world at large. For this reason, the government needs to take swift measures to be able to manage the situation. First, the government can increase taxation levels on individuals and corporations. This will avail more revenues to repay the debt. Moreover, the government can cut on its public spending, so that the saved amounts of money can be used to repay the debt. The last option would be establishing a consolidated sinking fund, which will help to break the vicious cycle of borrowing. These measures will help to improve and reduce the national debt levels into manageable and sustainable levels.

Definition essay Trust - 1338 Words

4/1/14 English Composition Definition Essay: Trust What is trust? The dictionary meaning of trust is a firm belief in the reliability, truth, ability, or strength of someone or something. The second meaning is, confidence placed in a person by making that person the nominal owner of property to be held or used for the benefit of one or more others. But what can we really define as trust? In this paper, I will discuss how trust is used every day in different situations, how we deal with trust in various relationships, and how we as individuals practice trust within ourselves. There are many different kinds of examples of trust. Some include, trust in your family, trust in your†¦show more content†¦Therefore, the top head of any company puts trust in his or her employees to get the job as well. Putting trust in God is another example of trust. This is a type of trust that is very complex. Non-believers do not seem to understand how we can put our trust into someone we cannot see. With faith comes trust, and as we grow in our faith, trusting comes a lot easier every day. We put our trust in the Bible and trust that everything that is said in it is true. This is a form of trust that is different than trusting people who you have earthly relationships with. We often confide in different passages and scriptures in the Bible to see examples of how we should trust God. One example of trust in the Bible is the story of Joseph. Joseph was sold into slavery by his own brothers, who he trusted, and became sold to Potiphar, the official in Pharaohs household. After being thrown into prison by Potiphar for being accused for raping Potiphar’s wife, he worked hard and became in charge of the prisoners. Pharaoh then had a dream, and the dream could only be interpreted by Joseph because God blessed him with that gift. After interpreting the dream, he became in charge of all of Egypt under pharaohs command. Joseph’s brothers traveled to Egypt to buy food, and there he revealed himself to his brothers and they apologized to him for what they did to him. Josephs forgave them and sent for his father Jacob and the rest of hisShow MoreRelatedAnalysis Of Burning Love By Elizabeth Kolbert1390 Words   |  6 Pages published in the New Yorker on December 5, 2011 she argues that although fracking has made individuals and businesses wealthy, it should be banned. In this essay, I will analyze Elizabeth Kolbert’s essay by identifying and detailing her purpose, goal, audience, and four rhetorical strategies used in this article. Elizabeth Kolbert’s essay was published in the New Yorker making the audience 57% democrat, with an average age from 30-49 and 50-64. 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There have been articles, essays, poems, and even books written about this subject. Transcendentalism has effected many people since the philosophy was first introduced. The idea was complex and hard to grasp for many commoners and therefore it was understood by few people, and someRead MoreMy Experience As A Preschool Teacher862 Words   |  4 PagesMajor Personal Essay: Trust in the Educational Experience How important is trust to the educational process? How does trust between student and teacher impact the experience for both? Over the years, I have sat the chair of both student and teacher, although not typically at the same time! Pondering the topic of trust in the educational experience, I am aware of an internal dialog that is not unlike the Disney Pixar movie, â€Å"Inside Out†. 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Nietzsche mostly talks about how man deciphers truth in his essay; however Nietzsche cannot avoid mentioning lying because in reality, lies and truth are very intertwined with each other. In fact, there are times when the truth and lies are so entangled that there are indecipherable from one another. If there isRead MoreLeadership Qualities Of An Effective Leader1075 Words   |  5 Pages Leadership: the definition states that someone in the position of leader, who guides or directs a group. This definition is hauntingly broad to me. Leadership, I believe, is not an idea that can be defined. It is instead an exemplary action by a single person whose best interest lies with the betterment of the group, and not himself. The qualities of an effective leader are apparent in Lord of the Flies. As for an effective leader in today’s society, this essay will analyze the leadership qualities

Bullying Prevention And Treatment Of Bullying - 1289 Words

The Chapter 13 article emphasizes that teachers hold the key to change through successful prevention and treatment of bullying. Teachers are essential where their own behavior and interactions with students are critical to enhance their development. In order to eradicate or prevent bullying, teachers need to be aware and recognize that bullying is a serious problem. Although appropriate action is taken when bullying occurs, this topic will continue to be a painstakingly issue to solve. The Anti-Bullying Research and Resource Centre at Trinity College in Dublin received a letter from a concerned parent in regards to her son being bullied. The parent spoke to the principal and staff members who were nonchalant about the bullying. The Anti-Bullying Centre provides information, advice, and guidance on the problems of bullying. Despite the widespread publicity that bullying receives, individual teachers and school administrators fail to acknowledge the subject as a problem. The nationwide study comprised of over 20,000 students from primary and post-primary schools. The students were given questionnaires which they had to answer about the different aspects of bullying. The results of the nationwide study were difficult to comprehend since the validity of the numbers is unknown. Unfortunately, the inaccuracies of the data will have research analysts ponder whether the questionnaire answers are truthful or unreliable. When the extent of peer bullying and victimization areShow MoreRelatedPlanning Health Assessment1180 Words   |  5 Pagesunder 18. Bullying as a Health Concern Not many people would think that bullying can be considered a serious health concern, but it is and it is an ongoing problem. 2010 statistics show that 2.7 million kids get bullied yearly and 2.1 percent become bullies. Statistics also show that 1 in 7 have either been a bully or was bullied from grades K-12. â€Å"In fact, revenge for bullying is one of the strongest motivations for school shootings, according to recent bullying statistics† (Bullying StatisticsRead MorePrevention And Intervention Of Bullying Behaviors918 Words   |  4 Pagesa major role in prevention and intervention of bullying behaviors. Studies repeatedly suggest that bullying can be significantly impacted if teachers, students, student groups, administrators, and parents worked together to stop bullying (Mount, 2005). Social services can be useful through afterschool programs, specifically educating youth who might be at a greater risk of bullying and victimization. Social services can also work with parents to discuss parenting styles and attachments. Based onRead MoreSchool Wide Approach For Addressing School Bullying Prevention Program951 Words   |  4 Pagesschool bullying (Aluedse, 2006). 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We typically don’t think about the consequences of bullying, but studies have shown that students who are bullied at school in grades 7-12 are 50% more likely to abuse substances (Promises Treatment Center). Bullying is the act of physical or verbal tormenting over a set amount of time, usually targeted at one person or a group of people. Bullying is an internationalRead MoreCauses and Solution of Juvenile Delinquency in America Essay1726 Words   |  7 Pagesage of 18† (Khan).Juvenile delinquency can be caused by the influence gangs,bullying, and bad parenting. This topic caught my attention because there a lot of kids getting arrested each year for crimes committed and kids getting involved in gangs, also kids getting access to weapons,drugs, or getting bully by other people. However juvenile delinquency can be prevented by offering bullying prevention, violence prevention curriculums and mentoring programs. â€Å"If gangs are dealing drugs or sellingRead MoreBullying: A Repetitious Epidemic Essay1606 Words   |  7 Pagesâ€Å"New bullying statistics for 2010 revealed about one in seven students in grades kindergarten through 12th grade is either a bully or has been a victim of bullying† (â€Å"Bullying Statistics 2010†). How does a person detect whether someone is being bullied? â€Å"A person is bullied when he or she is exposed, repeatedly over time, to negative actions on the part of one or more other persons, and he or she has difficulty defending himself or herself† (Olweus). Bullying takes place more in middle school becauseRead MoreBullying Victimization And Its Effects1469 Words   |  6 PagesINTRODUCTION The definition of bullying victimization is most often attributed to Daniel Olweus; who defined bullying victimization as an act in which a person is exposed to negative actions that are intended to inflict physical, mental or emotional distress (Olweus, 1994). One of the most significant consequences of bullying victimization is the observation that it occurs most often in repeated cycles that can affect the long-term emotional stability of the victim (Nansel, Overpeck, Haynie, RuanRead MoreBullying Victimization And Its Effects1446 Words   |  6 PagesThe definition of bullying victimization is most often attributed to Daniel Olweus; who defined bullying victimization as an act in which a person is exposed to negative actions that are intended to inflict physical, mental or emotional distress (Olweus, 1994). One of the most significant consequences of bullying victimization is the observation that it occurs most often in repeated cycles that can affect the long-term emotional sta bility of the victim (Nansel, Overpeck, Haynie, Ruan, Scheidt,

Safeguarding And Protection Of Vulnerab Free Essays

string(83) " to access the protection of the law and legal processes where they wish to do so\." To protect somebody is to keep them safe from harm and injury and the term safeguarding means to protect from harm or damage with appropriate measures. As a person’s mental capacity is relevant with regards to safeguarding, as a worker, you have to accept that an adult is making choices that to you may be unwise, but If they are deemed to have mental capacity, there is very little you can do apart from advise them of this. As adult safeguarding is not â€Å"clear cut† you have to ensure that you do not think the decisions they are making are unwise because you yourself wouldn’t do it. We will write a custom essay sample on Safeguarding And Protection Of Vulnerab or any similar topic only for you Order Now The majority of our client group are vulnerable, and if we look at the adults that e work with that misuse substances, this can be a grey area with regards to safeguarding. Obviously if an adult chooses to use a substance, that is their decision, however, substances impair your mind and your Judgment, so if something happens to them whilst they are under the Influence, this should be a safeguarding matter and should be dealt with accordingly. By protecting somebody this could imply that others are making a decision for an adult rather than with them, but the current safeguarding legislation in place accepts that individuals have the right to take risks o long as they have capacity and understand the implication or consequences. An example of this would be a client who we are currently working with who is a dependent alcoholic with cataracts in both eyes so he has virtually no sight. This man Is extremely vulnerable to theft and people taking advantage of him. The work that we do to protect him wealth the home Is practical things Like removing trip hazards, putting things back exactly where they are in the flat and guiding him when we take him out shopping. This man became the subject of safeguarding when somebody knocked his door claiming to be a council official and demanded that he ay all of his Council tax arrears. Secondly, one of his â€Å"friends† used to do his shopping for him but this has resulted in money going missing from his bank account. This gentleman does have mental capacity although this has to be questioned if he has decided to drinks whole bottle of vodka. Although it is not good for him, it is his decision to drink alcohol and that has to be respected. We can advise him of the risks to his health and how this could put him in vulnerable situations. We can protect him from his friend having access to this bank account by owing shopping for him, however, If he refuses this request, we can only make him aware that money may well go missing again. We all have a duty of care towards our Child Protection, different social care teams can have very different views/opinions on what is a safeguarding matter. . 3 Explain the legislative framework for safeguarding vulnerable adults There are many Acts and Government initiatives in place with regards to vulnerable adults safeguarding. Human Rights Act (1998) – This Act is a benchmark upon which services can assess how they uphold an individuals rights. Public bodies such as Police, Courts, hospitals etc, and other bodies carrying out public functions have to comply with the Convention right s. The list below details the fundamental rights and freedoms that individuals have access to. Everyone has a right to life, a life with freedom from torture and inhuman or degrading treatment. A right to liberty and security, freedom from slavery and forced labor. The right too fair trial with no punishment without law. Respect for your private and family life, home and correspondence. Freedom of thought, belief and religion and freedom of expression. Protection from discrimination in respect of these rights and freedom. Freedom of expression and the right to marry and start a family. The right to peaceful enjoyment of your property and the right to education. Care Standards Act (2000) – this led onto National Minimum Standards and means of measuring care service quality. This act has established an independent regulatory body for care services, (the National Care Standards Commission). Independent Councils are required to register Social Care Workers, set standards in social care work and regulate the education and training of Social Workers. It provides for the Secretary of State to maintain a list of individuals who are considered unsuitable to work with vulnerable adults. The main purpose of the Act is that local authorities will be required to meet the same standards as independent sector providers. The Act made for the provision of a General Social Care Council whose role it is are to regulate the training of Social Workers, raise standards in social care through codes and conduct and practice with a register of social care staff to be set up and maintained by the council. Care providers who supply individuals to work in care sections will be under a duty to refer people to the list who are considered unsuitable to work with vulnerable adults. Care providers have to carry out checks of the list before offering employment in a care position working with vulnerable adults and should refuse employment to any person. No Secrets (2000) – This guidance was produced due to serious incidents of abuse and to also ensure compliance with the Human Rights Act. Although No Secrets is not legislation it holds the status of statutory guidance and local social services should follow this. The key statements in relation to No Secrets are; Every person has he right to live a life free from abuse, exploitation and neglect. There should be no discrimination regarding abuse because of assumptions about class, gender, age, disability, sexual orientation, race, religion or culture. Adults at risk of abuse must be made aware of their rights and given information, advice and support. They should be enabled and encouraged to access the protection of the law and legal processes where they wish to do so. You read "Safeguarding And Protection Of Vulnerab" in category "Papers" Every effort must be made to promote the well being, security and safety of adults at risk of abuse in line with their rights, mental capacity n the course of action to take whilst being given all possible forms of support. An adult may choose to remain in an abusive environment, and, in such cases it is important to consider what advice and support can be offered to reduce the risk of harm. Effective inter agency working is crucial for the safeguarding of adults from abuse. Effective information sharing, collaborations and understanding between agencies and professions are paramount in safeguarding adults. No single agency can act in isolation to ensure the welfare and protection of adults at risk of abuse and information and decision making must be shared. Valuing People (2001) – This is specifically related to those with learning disabilities and has been written from a human rights perspective and also started the personalization agenda. It includes the several key rights; People with learning disabilities and their families have the same human rights as everyone else. Independent Living – All disabled people should have greater choice and control over the support they need to go about their daily life. They should have greater access to housing, education, employment, leisure and transport and be giving the opportunity to participate fully in family and community life. Control – People with disabilities are to be involved and in control of decisions made about their life. They are to be provided with the information and support to understand the different options and consequences so that they can make informed decisions. Inclusion – Being able to participate in all the aspects of community. To work, learn and meet people. To become part of a social network and be able to access services and have the support to do so. Safeguarding Adults (2005) – The aim of this was to change the concept of protection and was geared towards those who lacked capacity. This is where the concept of upgrading emerged with individuals taking informed risks and exercising choices rather than authorities taking the lead. Safeguarding Adults (2005) is made up of eleven sets of good practice standards. Each local authority has established a multi agency partnership to lead in safeguarding adults work. Accountability for and ownership of safeguarding adults work is to be recognized by each partner’s organizations body. The safeguarding policy includes a clear statement of every individual’s right to live free from abuse and neglect, this message is to be actively promoted to the public. Each partner agency should have a policy of zero tolerance of abuse within the organization. The safeguarding adults partnership oversees a multi agency workforce that is appropriately resourced with a development and training strategy. Anybody can access information about how to gain safety from abuse and violence to include information about local safe guarding procedures. There is a local multi agency safeguarding adults policy describing how local authorities respond to all adults who may be eligible for community care services and who may be at risk of abuse of neglect. Each partner agency has a set of internal guidelines that are insistent with the local authority safe guarding adults policy. The guidelines set out the responsibilities of all employees/workers. The safeguarding adults procedures include the following stages – alert, referral, decision, safeguarding assessment monitoring. The safeguarding procedures are available to all adults covered by the policy. The partnership agency includes service users in all aspects of their work. To include monitoring, development, implementation of safeguarding plans and assessment. Mental Capacity Act (2005) – This Act is aimed to protect vulnerable adults who are enable to make their own decisions and it has 5 key principles. Presumption of capacity – every adult has the right to make his or her own decisions and must be assumed to have capacity to do so unless it is proved otherwise. You cannot assume that somebody cannot make a decision for themselves Just because they have a particular medical condition or disability. Individuals being supported to make their own decisions – A person must be given all practicable help before anyone treats them as not being able to make their own decisions. You should make every effort to encourage and support people to make their own decisions. If lack of capacity is established, you should still involve the person as much as possible in making decisions. Unwise decisions – People have the right to make unwise decisions that others may think are unwise or eccentric. You cannot assume a lack of capacity for this reason. People have their own values, beliefs and preferences which may not be the same as others. Best interests – anything done for or on behalf of a person who lacks mental capacity must be done in their best interests. Less restrictive option – Someone acting on behalf of a person or making a decision for a person who lacks opacity must consider whether it is possible to act in a way that would interfere less with the person’s rights and freedoms of action and whether any decision/action needs to be taken at all. Any intervention should be weighed up in the particular circumstances of the case. Safeguarding Vulnerable Groups (2006) – This saw the introduction of the vetting/ barring system and the introduction of the offence fraud by abuse of position. It has the following three key principles. Unsuitable persons should be barred from working with children or vulnerable adults. Employers should have a means of heckling that a person is not barred from working with children and vulnerable adults. Suitability checks should be part of an ongoing assessment in order to catch those who commit wrongs following a suitability check. Fraud Act (2006) – This included a new offence of fraud by abuse of position. This included the misuse of money by those appointed to manage money, for example power of attorney or a position that an agency was expected to safeguard and not to act against the financial interests of another person, or people that have abused their position. Deprivation of Liberty Safeguards (2008) – This is part of the legal framework that is et out in the Mental Capacity Act. Those unable to consent to treatment due too mental impairment should be supported in a way that does not limit their rights. It was introduced to protect the human rights of people who were in certain settings does not apply to people who have been detained under the Mental Health Act 1983. Deprivation of Liberty should ensure that people can be given the care they need in the least restrictive regimes, prevents decisions that deprive vulnerable people of their liberty and allows people the right to challenge against an unlawful detention. Health and Social Care Act (2008), (Regulated Activities), Regulations 2010 and the Care Quality Commission (Registration) Regulations 2009 – This led to the creation of the Care Quality Commission to regulate services using the essential standards of quality and safety, with the emphasis on outcomes and what can be expected from care providers. The regulations in relation to safeguarding are; Respecting and involving people who use services. Consent to care and treatment and a client can be confident that their human rights are respected and taken into account. Care and welfare of people that use services – roper steps must be taken to ensure that each client is protected against the risks of receiving care or treatment that is inappropriate or unsafe. Safeguarding people who use services from abuse – suitable arrangements should be made to ensure that clients are safeguarded against the risk of abuse by taking reasonable stops to identify the possibility of abuse and prevent it before it occurs and respond appropriately to any allegations of abuse. Cleanliness and infection control – measure must be taken so far as reasonable practicable to ensure that clients and workers are protected against identifiable risks of infection. Management of medicines – clients are to be protected against the risks associated with the unsafe use and management of medicines. Appropriate arrangements are to be made for obtaining, recording, handling, using, safe keeping, dispensing, safe administration and disposal of medicines. Safety and suitability of premises – We must ensure that clients and workers that have access to premises are protected in that the design and layout is suitable and appropriate security measures have been taken. Safety, availability and suitability of equipment – Suitable arrangements must be made to rote clients and workers who may be at risk from the use of unsafe equipment. Equipment must be properly maintained and suitable for its purpose and must be used correctly. Requirements relating to workers – Companies to ensure that the person is of good character and has the relevant skills and experience to do the work and to ensure that the necessary checks, (DB’S), have been carried out. Supporting Workers – Workers should be supported by their Managers to ensure that they are appropriately supported in relation to their responsibilities to ensure they do their job to the required standard. Assessing and monitoring the quality of service provision – this should be regularly reviewed and clients should benefit from safe quality care, treatment and support in relation to decision making and the management of risks to their health, welfare and safety. Notification of other incidents – the commission must be notified of any incidents which occur whilst services are being provided. In relation to safeguarding this is any abuse or allegation of abuse that has been made or any incident which is reported to, or investigated by, the police. Reemerging from vulnerable adult to adult at risk. The Government are due to consider the recommendations with a view to introducing legislation. The recommendations are as follows; Local social services have the lead in co ordination responsibility for safeguarding. Local authorities have a duty to investigate adult protection cases And can either do this themselves or refer the investigation to another agency but this must be monitored by them. The local authorities would have the power to request co operation in adult protection investigations. An adult at risk can be defined as a person who appears to have health or social care needs, the person must appear to e at risk of harm rather than significant harm, the person appears unable to safeguard themselves from harm due to their health and social care needs. Harm is defined as ill treatment, (to include exploitation that is not physical), the impairment of health and development, self harm and neglect and unlawful conduct that affects a persons property, rights or interests. Local authorities should have the lead role in establishing and maintaining safeguarding boards. The local authority, NASH and Police would be required to nominate a safeguarding board member that has the appropriate knowledge and skills. New compulsory and emergency powers should be set out for local authorities and adult protection cases, for example, power of entry or exclusion orders. Statement of Government Principles on adult safeguarding (2011) – local multi agencies should support and encourage communities to find their solutions locally. Guidance is given on how principles can be turned into outcomes. The six principles are; Empowerment – presumption of person led decisions and informed consent. Protection -support and representation for those in greatest need. Prevention – it is better to take action before harm occurs. Proportionality – proportionate and least intrusive response appropriate to the risk presented. Partnership – Local solutions through services working with their communities. Communities have a part to play in preventing, detecting and reporting neglect and abuse. Accountability – Accountability and transparency in delivering safeguarding. 1. Explain the protocols and referral procedures when harm or abuse is alleged or suspected Within Sad/Alpha we have a Vulnerable Adult safeguarding lead. When a worker has concerns or a client has alleged abuse/harm, the first point of contact would be to discuss this with their Manager, (this should be no later than the end of he day that the allegation was made or the incident happened). If the client had made an allegation, whilst the worker was with them, they would make a factual note of what has been discussed, this would include name, date, details of allegation made and the worker’s response. It is important that the client feels trusted and that no leading questions are asked. The worker should then advise the client that they will be discussing this with their Line Manager as they have a duty of care towards them. Depending on the situation that has occurred, the worker would need to ensure that the adult at risk is made safe and if required has received medical occurred with a view to discussing whether the Police should be informed of this. If a worker has concerns about a client but an allegation hasn’t been made, the worker is advised to speak to their Line Manager regarding this. As soon as realistically possible file notes should be done and together, the Manager, the Vulnerable Adult safeguarding lead and the worker will agree on the next course of action that needs to be taken. It is at this point it is important to remember that if the Manager and the worker do not agree on the next course of action then they are able to go to Senior Management level to discuss this further. . Sad/Alpha is a non statutory agency so, if we do have a concern regarding abuse, we would refer this onto the statutory agency that is working with the client. We would contact them as soon as realistically possible and follow this up with a written file note. If there is no statutory agency involvement, we would contact the Adult Social Services Locality Team to advise them of our concerns. This will usually mean speaking to the Duty Officer for the team. We would then follow this up with a written file note and send this across to the Duty Officer. Sometimes the Locality Team will check on their system, and, if there has been statutory agency involvement we were unaware of, they would request that we refer the matter to the relevant agency involved. Sometimes when a statutory agency, (for example SCHISM), have advised that they will be taking no further action and we disagree with this, we would then go back to the relevant Locality Team. They may well agree with the decision that has been made, and, if this is the case we would Just file note it accordingly. If however, they decide that action does need to be taken, it is the role of the Locality am to lead on this with the statutory agency. Internally, the seriousness of the incident will need to be assessed by the Manager and the Vulnerable Adult lead. If the incident is considered to be minor, we would complete a sudden untoward incident form and still advise the lead statutory agency Within Alpha is it my responsibility to ensure that all staff have been trained in Vulnerable Adult Safeguarding and that they are all aware of the reporting procedures/paperwork that needs to be completed. All workers know that any concerns have to be reported directly to myself, and, if I am absent, be reported to my Manager. The workers know that they are responsible for informing me as soon as possible and following this up with a written file note. They are aware that this type of information can be shared and that client confidentiality can be broken in this instance. Everything to do with the concerns raised or allegations made is documented in a file note and locked away in a secure filing cabinet. It is my responsibility to ensure that everything has been documented and stored. Safeguarding and the prevention of abuse As mentioned above, Sad/Alpha have a Vulnerable Adult Safeguarding Lead that I will liaise with if a safeguarding concern as been brought to my attention. It is mandatory for all staff to attend Vulnerable Adults Safeguarding training. Sad/Alpha have written their own company policies in relation to safeguarding. The safeguarding policy itself defines an adult at risk of harm, lists the types of physical/mental abuse or harm that can occur and the reporting procedure that should be followed if an allegation is made or if they have any concerns, (as outlined above). All staff who have read the policy will be aware of who they need to report to in the first instance and the importance of writing down and recording factual file notes. These policies have been written in line with the No Secrets Act (2000), The Mental Capacity Act (2005), Human Rights Act (1998) and Safeguarding Adults (2005). The other policy that needs to be read and understood in connection with safeguarding is the Sad/Alpha Weightlessness policy. This policy firstly reassures a staff member that they can make a disclosure within a positive and supportive environment and that there will be no reprisals from bringing a matter to their Manager’s attention. The reporting procedure is outlined in the policy, and if the member of staff has a concern about a colleague, they will report directly to their Line Manager. If, however, the concern is in relation to their Line Manager, they will report the matter to Senior Management level to be investigated. All staff are aware that they have a duty of care towards clients, their colleagues and themselves. I do believe that risk assessments that are regularly reviewed are extremely important to try and prevent abuse occurring. Alpha risk assessments covers areas such as historical risk, risk to self, risk to others, risk from others and environmental risks. When we assess a client we will complete a risk assessment form and the client will be marked for overall risk. We can then discuss with the relevant worker/professional how to minimize risk, for example, one of our clients has historically made an allegation of sexual assault against a male worker from another agency. This client is currently being seen in pairs and the two workers are female. Risk assessments will only be successful if they are reviewed regularly as a matter of course. Communication is also very important, not Just between other agencies, but within the team. All staff members must know who to report concerns to and what to do. If a Manager is made aware of a possible concern/risk, this must be passed onto the rocker and vice versa. All complaints must be investigated, (no matter how small or minor they appear to be), they must be documented correctly and the necessary action must be taken if required. Within Alpha we always encourage staff to try and view a complaint as a positive thing rather than a criticism. By reviewing and investigating complaints, our Care plans are also important in relation to safeguarding and these will also only be successful if they are reviewed on a regular basis and are communicated clearly to all staff that are working with the client. For example, we are currently working with a an who has poor eyesight and is unable to use the cash point unsupervised. Unbeknown to him, his friends have been withdrawing money from his account. His care plan has now changed in the respect that we have temporary power of attorney of his money and make all cash withdrawals at the bank for him keeping an accurate record of all money that has been spent. Sad/Alpha also have a responsibility to follow up on any references when people apply for a Job and to ensure that workers are not working with a client unsupervised until they have had a satisfactory DB’S check. Regular training and supporting staff on a regular basis is also key. 4. Recommend proposals for improvements in systems and procedures in own service setting Within Alpha, I believe that we are very good at communicating with each other and as a team. I would however like to improve this by coming up with regular training sessions/staff meetings where we can all get together and share our thoughts and ideas and that staff and Managers can be updated on what is happening with regards to all clients to include risks and safeguarding. I like to hold supervision regularly, and as part of supervision, we discuss the clients that the worker is currently seeing, we review their care plan and make any required changes. This would also be a good time to update risk assessments, but all staff are aware that anything in relation to risk should be brought to my attention as soon as possible and that they should not wait for a supervision. I do receive daily feedback from staff in relation to their visits. However, I would like to be more â€Å"hands off’ with regards to client work and be able to spend my time working with staff on their visits and also visiting clients to perform an audit of our services and this would include risk. The audit could then be shared with the worker who would know that they loud need to action any of the relevant points and feedback to me when this had been completed. I think this would be of benefit to the client and to the worker who would be mindful that regular audits were going to occur which, in turn, would make them more aware that policies and procedures do need to be adhered to and it reinforces our duty of care. I think that our policies and procedures as a company are fairly robust, however, these may be subject to change in the near future if adult safeguarding becomes statutory along the same lines as child protection. I have now adopted a system, that should there be a change in risk, a new risk assessment form is completed. I would however like to visit the clients on a quarterly basis at least to re evaluate risk regardless of whether their circumstances have changed or not. Although our team has a case load of regular clients, I believe that it is important that they are occasionally seen by somebody else who is not so used to them. It is very easy to become blinkered to risk/harm and a new set of eyes can be very important when reviewing this. I would like to implement a regular shuffle around within the unit/AC Learner signature: Assessor signature: Date: How to cite Safeguarding And Protection Of Vulnerab, Papers

Settling in at University

Settling in at University Starting university, particularly if you are moving away from home, can be an overwhelming experience.   There are, however, several ways to feel settled as quickly as possible, so that you can concentrate on your studies.   Here are the top tips for feeling at home and settling in at university. Make your university accommodation feel like home. Bringing your own bed covers and cushions will instantly make your new room feel like it belongs to you.   It's also great to add things like photographs of family or friends if you are living far from home.   Organise all your clothes, food, and kitchen utensils so you can find everything you need easily. Make sure that photo of your loved one is next to your bed for when you wake up in the morning.   Look after yourself. It can be tempting to drink far too much, live on a diet of junk food and get no exercise. However, indulging too much in alcohol and fatty food will leave you feeling tired and sluggish, and you'll put on weight at the same time.   Cook simple meals and make a point of going for a walk or taking some other form of exercise every day. You want to be able to pay attention in your lectures and tutorials, and making sure you eat properly and sleep well are instrumental in being able to do this. Structure your time. It's great to socialise and make new friends, but you need time to yourself too when settling in at university.   It's equally good to work hard at your studies, but you need to find a healthy outlet for stress as well.   To be able to do all this, you should allocate time for seeing friends, for studying and for having relaxing time to yourself.   Doing this will mean you perform well at your work, have a good social life and feel calm and centred.

Romeo - A Character Profile From Romeo and Juliet

Romeo - A Character Profile From Romeo and Juliet One of the original star-crossd lovers, Romeo is the male half of the ill-fated pair who drive the action in Shakespeares Romeo and Juliet. Much has been written about the origins of the character, and the influence Romeo has had on other young male lovers throughout Western literature. But Shakespeares Romeo is an enduring representative of young love gone tragically wrong.   What Happens to Romeo Most interpretations of Romeo and Juliet estimate him to be about 16 years old, and Juliet to be about 13.  The heir of the House of Montague, Romeo meets and falls in love with Juliet, the young daughter of the House of Capulet. For reasons unexplained, the Montagues and Capulets are bitter enemies, so the young lovers know their affair will anger their families.  But the titular couple isnt interested in family feuds, and quickly fall in love.    Romeo and Juliet secretly marry with the help of his friend and confidant, Friar Lawrence. But the two are doomed from the start; after Juliets  cousin Tybalt kills Romeos friend Mercutio; Romeo retaliates, killing Tybalt. He is sent into exile, only returning when he hears of Juliets death. But Juliet has only faked her death unbeknownst to Romeo, who kills himself in a fit of grief. She awakens to find him dead and takes her life, this time for real.   Was Romeos Death Fate? After the young lovers die, the Capulets and Montagues agree to end their feud. Shakespeare leaves it mostly to his audience to decide whether this means that Romeo and Juliets deaths are fated. Could the feud have been ended any other way?   Questions long debated among Shakespearean scholars: Is the outcome of the play the result of bad luck? Or were Romeo and Juliets deaths predestined as part of the legacy of their families feud? Origins of the Romeo Character Most Shakespeare historians trace the origin of the Romeo character back to Greek myth. Ovids Metamorphoses  tells the story of Pyramus and Thisbe, two young lovers in Babylon who lived next to each other and communicated through cracks in the walls, their parents having forbid them meeting because of an ongoing family feud. The similarities to Romeo and Juliet dont end there: When the pair arrange to meet finally, Thisbe arrives at the predetermined spot, a mulberry tree, to find a menacing lioness. She runs away, but accidentally leaves her veil behind. Pyramus finds the veil when he gets there and believes the lioness has killed Thisbe, so he falls on his sword (literally). Thisbe returns and finds him dead, then kills herself with his sword.   While Pyramus and Thisbe may not have been Shakespeares direct source for Romeo and Juliet, it was certainly an influence on the works from which Shakespeare drew. Romeo first appeared in Giulietta e Romeo, a 1530 story by Luigi da Porto, which was itself adapted from Masuccio Salernitanos 1476 work Il Novellino. All of those later works can, in some way or other, trace their origins to Pyramus and Thisbe.

Bridget Riley Biography

Bridget Riley Biography Bridget Riley began working in the Op Art movement far before it was named as an official artistic movement. Still, she is best known for her black and white works from the 1960s that helped inspire the new style of contemporary art. It is said that her art was created to make a statement about absolutes. It is coincidental that they are viewed as optical illusions. Early Life Riley was born on April 24, 1931, in London. Her father and grandfather were both printmakers, so art was in her blood. She studied at Cheltenham Ladies College and later art at Goldsmiths College and the Royal College of Art in London. Artistic Style After her early, extensive artistic training, Bridget Riley spent several years casting about for her path. While working as an art teacher, she began exploring the interplay of shape, lines, and light, boiling these elements down to black and white (initially) in order to fully understand them. In 1960, she began working in her signature style - what many refer to today as Op Art, a display of geometric patterns that tricks the eye and produces movement and color. In the decades since, she has experimented with different mediums (and color, which can be seen in works like 1990s Shadow Play), mastered the art of printmaking, moved through differently shaped themes, and introduced color to her paintings. Her meticulous, methodical discipline is phenomenal. Important Works Movement in Squares, 1961Fall, 1963Dominance Portfolio (Red, Blue and Green) (series), 1977Ra2, 1981Conversation, 1993

Financila Performance and Positioning Assignment

Financila Performance and Positioning - Assignment Example A projected profit and loss account of Clinton Cards plc has also been included in this part to add to the analysis. Shareholders need to analyse the management's performance and efforts put into the company affairs through the financial results so as to realise its strengths and weaknesses. Riahi-Belkaoui (1998, p11) says, "the profitability ratios portray ability of the firm to efficiently use the capital committed by stockholders and lenders to generate revenues in excess of expenses". Therefore, the analysis for the shareholders has been done with the help of following profitability ratios: The above chart depicts the profitability ratios for Clinton Cards plc indicating the financial performance of the company over the last five years. Shareholders are interested in the company's profit records and being the real owners of the firms, they constantly need to appraise the company's performance. If the company is able to generate a stable profit for its shareholders out of its business activities, then it is said to be a good performer in the financial sense. The Gross Profit Margin Percentage evaluates the percentage of profit earned by a company on sales after the production and distribution activities (Mcmenamin, 1999). It shows how well the company manages its expenses so as to attain maximum profit out of its total sales. Clinton Card plc's gross profit ratio shows that the company is sustaining a stable profit margin with a slight increase in profitability. It further illuminates that the company manages to keep about 11% of its total sales revenue out of all the production and distribution expenses. This can also be inversely stated that the company loses about 89% of the total turnover in meeting cost of sales. The Net Profit ratio shows what percentage of profit a company earns on its sales (Mcmenamin, 1999). It reveals the profit retained by a company after accounting for its various operating costs. The difference between the company's net and gross profit ratios indicate the amount of profit foregone by them in the course of meeting various selling and administrative expenses. Thus the above graph shows that the company manages to retain about 6% of the total sales after accounting for various operating costs. The company's net profit margin is also rising sparingly at a stable rate showing the management's efficiency in managing costs. Riahi-Belkaoui (1998, p11) says that the return on capital employed ratio "indicates how efficiently the capital supplied by the common stockholders was employed within the firm". Clinton Card plc's return on capital employed ratio reveals that the company is having a slightly fluctuating rate of profit on the funds invested by the shareholders. However the rate of fluctuation is not high and thus the graph shows that the company gains profit as about 30% of the total equity funds. The return on asset ratio indicates the returns or profits generated after utilising the financial resources of the company determine the company's financial performance throughout the year (Meigs & Meigs, 1993). The company in consideration has had a significantly

Evaluative Review Assignment Essay Example | Topics and Well Written Essays - 750 words

Evaluative Review Assignment - Essay Example Recommendations Organize with parents to address ways to identify if their child has destructive tendencies According to Jimerson and Furlong (2006), this is a better way of dealing with a student’s aggressive behavior. Parents are better positioned to evaluate their children mannerisms and take the necessary measures. Education about the signs of this behavior will assist parents in taming their misdemeanor. Application of this will streamline a student’s morals and methods of associating with others. Parents are occasionally determinants of a child’s character development. Therefore, their children are more likely to take heed of their advice. Metal Detectors According to Jimerson and Furlong (2006), the employment of a metal detector in searches is highly advisable. It is in the interest of all students that this practice is approved. Some students who have malicious intentions towards the teaching staff or fellow comrades are capable of carrying weapons to th is effect. However, persons who do it should not abuse this activity. This measure will definitely discourage students from transporting harmful objects to schools. Metal detectors have proven effective in sectors such as airports and highly guarded government institutions. It has reduced potential threats such as terrorism and smuggling. Follow the law The law is a guideline of limitations and freedoms we should exercise. Teachers are to exercise acceptable disciplining methods of students who have behavioral cases (Conoley and Goldstein 2004). Disciplinary punishment should be implemented to the extent instructed by law. Excessive use of force in disciplinary cases often initiates some violent and rude behaviors from students. This can have extensive consequences as the student can resort to unconventional ways of coming even. Conoley also suggests that statistically, in many cases students win legal cases concerning discipline and the institution suffers the embarrassment. Teache rs should be more cautious on this issue. Training School Staff The schools staff both administrative and non-administrative is instrumental in ensuring proper safety precautions are adhered to (Conoley and Goldstein, 2004).Violence is impartial and occurs randomly in view of the supposition that it is intricate to determine a person’s intentions. Students have developed clever ways to conceal their intentions. Therefore, the staff including teachers, train guards and drivers should focus on violence prevention. The staff should be trained to take steps promptly when violence occurs. This will help them mitigate the adverse effects that associate to this vice. They should also be trained to detect destructive behavior in the initial stages thus enabling them prevents unavoidable that was to happen. According to Daniels and Bradley (2011), ignorance of the staff of growing tensions between students is what leads to the columbine High school riot. Violent incidences were ignore d based on the perpetrators social status in the institution. This allowed the popular and senior students assault their fellow junior scholars uncontrollably. The intimidated student’s collective anger led to the rampage. The staff was vindicated on their negligence of the spiteful activities that were occurring in that institution. Establishment of Good Trust relationship with Students According to Daniels and Bradley (2011), most of the students who partake in these acts have

Processes of Drugs Metabolism in the Body

Processes of Drugs Metabolism in the Body Abstract Metabolism of drugs is a complex and major process within the body, occurring primarily in the liver. The aim of metabolism is to make the drug more polar to enable excretion via the kidneys. The basic understanding of drug metabolism is paramount to ensure drug optimisation, maximum therapeutic benefits and a reduction in adverse effects. Essentially drug metabolism is broken down into two phases, Phase I and Phase II. Phase I is concerned with the biotransformation of compounds, and then transferred to Phase II. However, for some drugs this is the end of their metabolic journey in the body, as they produce more polar compounds which are readily excreted. Phase II reactions are where compounds are conjugated to produce more water soluble compounds for easy excretion. Phase I reactions are dominated by the Cytochrome-450 enzyme superfamily. These enzymes are found predominantly in the liver, which is the major site of drug metabolism. However, drug metabolism is not localised merely to the liver, there are other major sites at which this process occurs. Some of these sites include the skin, lungs, gastro-intestinal tract and the kidneys; close to all tissues have the ability to metabolise drugs due to the presence of metabolising enzymes. The most important enzymes are the cytomchrome-450 superfamily, which are abundant in most tissues. Inactive drugs with the ability to reconvert to the active parent drug once metabolised to exert their therapeutic actions are defined as prodrugs. They are classified depending on the site of conversion and actions (gastrio-intestinal fluids, intracellular tissues or blood). This report gives different study examples of such prodrugs and how their metabolism differs within the body, compared to their active metabolites. Individual drug metabolism may be affected by variant factors, such as, age or sex. Drug metabolism can cause an increase in toxcity. The bioactivation of a parent compound can form electrophiles that bind to proteins and DNA. Some of this toxicity can occur in Phase I metabolism e.g. acetaminophen. However, in some circumstances toxicity occurs in Phase II e.g. zomepirac, polymorphism can also cause idiosyncracity of certain drugs to be toxic. 1.1 Phase I Phase one, otherwise known as drug biotransformation pathway is generally broken into oxidation, reduction and hydrolysis. A reaction under this phase involves an addition of oxygen molecule aiming to improve the water solubility of drugs. As the result some metabolites from this phase can be extracted immediately if they are polar enough however at times a single addition of oxygen is not sufficient enough to overcome the lipophilicity of certain drugs and hence their metabolite from this phase has to be carried onto phase II for further reactions. Major example of Oxidation: Accounting for roughly 20 complex reactions the most important oxidative metabolic pathway dominating phase I is the cytochrome-P450 (CYP450) monooxygenase system processed by C-P450. Located primarily in the liver CYP450 was found to be present in all forms of organisms, including humans, plant and bacteria. It is important to note that the function of CYP450 goes beyond drug metabolism but it is also involved in metabolism of xenobiotics, fat soluble vitamin and synthesis of steroids. With substrate specificity of more than 1000 and its ability to produce activated metabolites such as epoxide are the underlying reason for its dominance and importance in drug discovery. The general mechanism the CYP450 monooxygenase oxidation is: R + O2 + NADPH + H+ à   ROH + H2O + NADP+ (fig 2) From the above formula it can be this reaction is of NADPH (Nicotinamide adenine dinucleotide phosphate) and an oxygen molecule dependent. As mentioned above oxygen is important to increase the water solubility and in the same manner NADPH is also important for oxygen activation and source of electron. Also important for activation of oxygen is the presence of cystine amino acid located near the protein terminal carboxyl of CYP450. Among the 500 amino acid present in CYP450, cystine has proven to be most important as it activates the oxygen to a greater extend. This is due to the fact that it contains a thiol group as one of its ligand and it is the thiol which alerts the reactivity. Highlighting the numerous intermediate structures involved as well as function of iron, oxygen and proton (Figure) shows the catalytic conversion required for cp450 oxidation reaction to place. The binding of the substrate with low spin ferric CYP450 enzyme induces a change in its active site. This will effects the stability of the water ligand and will displace it (shown in the diagram from a-b). Containing a high spin heme iron the enzyme and substrate form a ferric complex. The change in electronic state will result in the release and transfer of one electron from NADPH via electron transfer chain (reducing ferric heme iron to ferrous state) and thus reduction of the complex. The second electron is transferred when the complex reacts covalently with the oxygen forming a new ternanry complex. Initially the complex is an unstable oxy-P450(diagram d), however this is reduced to produce ferrous peroxide by a loss of an electron. This intermediate is short lived and undergoes protonati on twice resulting in a release one water molecule. Out of the oxygen molecules released one in incorporated in this water molecule and the remaining into the substrate. Another method of forming the iron-oxo intermediate is via the peroxide shunt which elimited steps from C to F. Some of the common addition of oxygen molecule reactions which CYP450 dependent are known as epoxidation (of double bond), N-hydroxylation, oxygen/nitrogen/ sulfur dealkylation, s-oxidation, dechlorination, oxidative desulfurisation and aromatic hydroxylation. Note they all follow the same principle of adding oxygen molecule to the substrate. The diagram below provides an example of how these reactions are processed: Aromatic hydroxylation substrate mostly produces phenols such as that seen on figure 3. The production of Phenol can be either via a non enzymatic rearrangement or by Epoxide hydrolase and cytosolic dehydrogenase which will ultimately give rise a catechol. The position of hydroxylation depends greatly on the nature of the R- group attached to the ring; an electron withdrawing group will position the -OH group on the metha while the electron donating will position it on the para or ortha. Aromatic hydroxylation also involves a change in NIH shift, which involves the movement and shifting of the R group to an adjacent position during the oxidation. It is important to note that certain substrate for aromatic hydroxylation can also be oxidized via the aliphatic (C-H) hydroxylation. Under such condition the aliphatic C-H) hydroxylation will oxidize it. Aliphatic dehydrogenation can also occur involving electron transfer to the CYP450. Currently more than 50 CYP-450 has been identified in human, however the bulk of drug metabolism is essentially carried by CYP1, CYP2 and CYP3 families, especially the CYP450-3A. The diagram on the right hand side clearly demonstrate just how much of drug metabolism is CYP450 3A responsibility in comparison to other, accounting for roughly 50%. Metabolism of drugs given orally are greatly determined by CYP450-3A primarily because this enzyme is present in both the liver and intestine and thus providing a barrier for all drugs before they can enter the systemic circulations, otherwise commonly known as ‘first pass effect. Upon entering the drugs are taken up via passive diffusion and/or facilitated diffusion or active transport into the entercocyte where they can be metabolized by CYP450-3A. They can once again be metabolized by the very same enzyme when they enter the liver (hepatocyte) ,which unlike the intestine in order to reach the systemic circulation it is unavoidable. Th is family of enzymes are also known to be cause of many serious adverse effects as they are influenced by diet and drug components, hence drug-drug and drug-food interactions is an important factor. Flavin monooxygenases Similar to cytochrome p450 monooxygenases system,Flavin monooxygenasesalso plays a major role in metabolism of drugs, carcinogens and Nitrogen/ sulfur/ phosphorous containing compounds. Also oxygen and NAPDH dependent, Flavin monooxygenases has much broader substrate specificity than CYP450. Once they have become associated with substrate the flavin monooxygenases is activated into 4ÃŽ ±-hyroperoxyflavin and unlike CYP450 the oxygen activation takes place without the need for substrate to bind to the intermediate. This pre-activated oxygen means that any compound binding to the intermediate is a substrate to be metabolized. The fact that this enzyme is able to remain stable and lacks any need for correct arrangement and disorientation of the substrate gives it ability to withhold all the energy required for the reaction to takes place and hence as soon as appropriate lipophilic substrate becomes available it starts the process immediately. Adverse side effects are rarely associated w ith these enzymes. The binding of oxygen to the reduced flavin is processed via a non-radical nucleophilic displacement. The substrate is oxidized via a nucleophilic attack by the oxygen that is located at end of 4ÃŽ ±-hyroperoxyflavin. This is then followed by cleavage of peroxide. The flavin monooxygenase catalytic cycle is finished once the original form of 4ÃŽ ±-hyroperoxyflavin has been regained using NADPH, oxygen and hydrogen proton. Note the metabolite product can at any times undergo reduction back to its original parent form. Alcohol dehydrogenase and aldehyde dehydrogenase These families of enzymes are both zinc containing NAD specific and catalyze the reversible oxidation of alcohol and aldehydes respectively. Grouped into 1-6 Alcohol dehydrogenase, are homodimer that exist in the soluble section of the tissue. It is involved in metabolism of some drugs such as cetirizine however it is more predominantly known as alcohol metabolism enzyme specifically ethanol, whether products of peroxides or that of exogenous (i.e administered drugs). It is important to note that although alcohol dehyrogenase is the main metabolic pathway for ethanol, however CYP2E1 also plays in its metabolism. CYP2E1 can be induced by ethanol resulting in adverse side effects between alcohol and with certain analgesics drugs. Alcohol dehydrogenase also metabolizes ethylene glycol and methanol. With a longer half life and rapid absorption from the gut, methanol can result in series of unpleasant side effects and metabolic acidosis, hence highlighting the importance of alcohol dehydr ogenase. Similarly, aldehyde dehydrogenase catalysis the oxidation of aldehyde to its corresponding carboxylic acid. Class one of alcohol dehydrogenase plays a major role in detoxification of anti cancer drugs. Alcohol dehydrogenase is also involved in reduction pathway of aldehyde or ketone back to its pharmacologically active alcohol form. Monoamine oxidase and diamine Located in liver, intestine and kidney as few of its site, this membrane bound enzyme is divided into two classes in accordance to their substrates specificity, they are monoamines-A and monoamine-B. Responsible for metabolizing amines via deamination to aldehyde, these enzymes are flavin containing enzymes and within their cysteinyl residue the flavin is linked to the covalently bounded flavin via a thioether. Monoamine oxidase has several substrates, ranging from secondary to tertiary amines that have alky group smaller than methyl. The general mechanism for this enzyme is the two electron oxidation shown below: R.CH2.NH2 + O2 + H2O à   R.CHO + NH3 + H2O2 (fig 7) As it can be seen this reaction requires oxygen to react and a hydrogen peroxide is produced as for every â€Å"one molecule of oxygen is absorbed for every molecule of substrate oxidized† (Principle of drug metabolism, 2007). Proportional to the rate of oxygen uptake this is commonly used to deduce the rate of reaction. Research has shown that monoamines-A is more commonly involved in oxidation of endogenous substrates such as noradrenalin while monoamine-B which is found mostly in platelets appears to catalyses exogenous substrates such as phenylethylamines. Their common substrate is dopamine. Inhibition of monoamine oxidase has long been of an interest for scientist in treatment of several of illness such as depression. Present in liver, lungs and kidney as few of its locations diamine oxidase also catalyses the formation of aldehyde from histamine and diamines in the same manner. Reduction This pathway of metabolism is enzymatically the least studied in phase I and yet it plays an important role in metabolism of disulfides and double bonds of for example progestational steroids as well as dehydroxylation of aliphatic and aromatic compounds. In general ketone containing xenobiotics are more readily metabolized and eliminated via this pathway in the mammalian tissue. This is due to the fact that the carbonyl group is very lipophilic, thus the lipophilicity will be reduced and elimination is ensured as ketone is converted to alcohol. One of the major enzymes involved in this pathway is the NADPH cytochrome P450 reductase. Containing flavin adenine dinucleotide and flavin mononucleotide is an electron donor playing an important role in the metabolism of drugs such as chloramphenicol by reducing its nitro group. Hydrolysis As the name suggests this pathway uses water to cause a breakage of a bond. Major enzymes under this pathway are the amide and ester hydrolysis and hence amide and esters are the common substrates. Naturally esters are much easier targets to esterase hydrolysis than amides. A very common amide substrate is a local anesthetic, Lidocaine and an antiepileptic drug known as levetiracetam. Catalyzing ester and certain type of amides are the group of enzymes referred to as carboxylesterase. This enzyme hydrolysis choline like ester substrate and procaine. As a rule, the more lipophilic the amide the better it be accepted as a substrate for this enzyme and thus eliminated. Esters that are sterically hindered are however much harder and slower to be hydrolysed and will usually be eliminated unchanged at a high percentage such as that for atropine, eliminated 50% unchanged. A very good example of esterase enzyme is the paraoxonase. The hydrolysis of substrate such as phenyl acetate and other acyl esters are catalyzed by this. For hydrolases and substrate to be involved in this pathway certain criterias are imperative for a fast reaction rate, these include having a electrophilic group a nucleophile that will attack the carbon attached to the oxygen resulting in a formation of tetrahedral orientation. The presence of a hydrogen donor to the improvers the leaving group abilities is the final requirement. 1.2 Phase II (Second part of drug metabolism): Second part of drug metabolism, involves introduinh of new ionic chemicals on to the substrate (including the metabolites from phase I) in order to increase its water solubilyt for elimination. This phase is usually refered to as conjugation reaction and its products are generally inactive unlike those of phase 1. The following reaction are major conjugation of phase II. Methylation is the transfer of methyl group to the substrate from cofactor s-adenosyl-L-methionine (fig 9). S-adenosyl-L-methione is an active intermediate that receives a transferred methyl group from methionine after its linkage with ATP in presence of adenosine transferase enzyme. It is this methyl group that is ultimately transferred on to the substrate. S-adenosyl-L-methionine methyl group becomes attached to the sulfonium center marking â€Å"electrophilic character† (Principle of drug metabolism, 2007). Depending on the functional group present on the substrate Conjugation via methylation is broken down to nitrogen, oxygen and sulfate methylation. O-methylation O-merthylation is the most common reaction that occurs for substarte containing the organic (formally known as pyrocatechol compound, catechol moiety) hence why the enzyme responsible for this type of reaction is called catechol O-methyltransferase. This Magnesium dependent, found cyclic but also, less frequently, as a membrane bound enzyme, is found commonly in liver and kidney among other tissues. Common drug for this type reaction are L-DOPA, where generally the methyl is transferred on to the substrate in meta position and less commonly para, depending the substituent (R group) that is attached on the ring. According to ‘Principle of drug metabolism the rate of reactivity of O-methylation is decreased in accordance to size of the substituted group, the larger it is the slower the rate of reaction degree of acidity of the catechol group itself. N-methylation Naturally this reaction has substrate specificity of amine, involving however primary and seconday only. Unlike the above reaction, N-methylation consists of several enzymes, all of which are categorized in accordance to the specific type of amine substrate which they catalyze. Enzymes such as amine-N-Methyltransferase, nicotinamide-N-methyltransferase and histamine-N-methyltransferase are few examples. Despite the substrate specificity all the enzymes involved do however follow the same principle of transferring methyl fromcofactor s-adenosyl-L-methionine to the substrate. With drug substrates such as captoril, reactions of N-methylation can be broken down into two distinct types as illustrated in Fig 11. Reactions that have a low pharmacological significant yield an ineffective n-methylation as the substrate and the product have a same electrical state thus the metabolites are usually less hydrophilic than parent. As it can be seen from fig 7a, in these reactions one proton is exchange for a methyl group. On the other hand a more hydrophilic product and an effective reaction of detoxification is achieved with pyridine type (nitrogen atom) substrate. These substrate will result in a creation of positive change on the product (fig 7b) rather than an exchange process. Sulfate and phosphate conjugation Sulphate conjugation is one of the most important reactions in biotransformation of steroids, effecting its biological activates and decreasing its ability for its receptor. Nucleophilic hydroxyl groups such as alcohol and phenol, primary or seconday amine and drug containing a SO-3 group are the common substrates for this pathway. Generally sulphate are transferred via a membrane bound enzyme named sulfotransferase (located in golgi apparatus) from their cyclic cofactor 3-phosphoadenosine 5 (shown in fig 8 ) to substrate. 3-phosphoadenosine 5 is formed in a reaction between adenosine triphosphate and inorganic sulfate where the sulfate/phosphate group are bonded via a anhydride linkage which gives rise an exothermic reaction when broken, hence providing the energy for the reaction. In human there is two class, SULT 1A- 1E and SULT 2A-2B, each of which will have different specificity yet with overlaps. This enzyme acts on both endogenous as well as exogenous compounds as long as they possess an alcohol (less affinity with varying product stabilities) or phenol (products are stable arly sulfate esters with a high affinity). Substrates are generally of medium sized, highly ionized and hydrophilic, hence excreted easier via urine. The rate of this pathway is determined by the lipophilicity and nature of amino acid present on the substrate. Interestingly phenol is also of an interest for the Glucoronic conjugation pathway and are metabolized by this when they are at high concentration and 3-phosphoadenosine 5 becomes rate limiting. The sulfate conjugation will produce ester sulfate or sulfamide some of which will undergo further heterolytic reaction leading to electrophilic substrate and hence toxicity. Unlike the sulfate conjugation the phosphate conjugation is less common unless the drug in question is anticancer or antiviral. Catalyzed phosphotransferases. conjugation The most important and major occurring metabolic pathway of phase II is the glucoronic conjugation, accounting for the largest share of conjugated metabolite in the urine. This pathway is important due to the fact there is a high availability of glucucronic acid, huge substrate specificity and the wide range of poorly reabsorbed metabolite. The glucoronic conjugation takes place as the glucoronic acid is transferred to the acceptor molecule from its cofactor uridine-5-diphosphh-alpha-glucoronic acid (fig 9 ) of which glucoroniuc acid is attached in 1 ÃŽ ± configuration. However products produced are in ÃŽ ²-configuartion. This is due to the nucleophilicity of the functional groups of the substrate. To be able to undergo this pathway of metabolism the functional group of drugs in question must have nucleophilic characteristics. Generally the drug that are at high affinity for this pathway is firstly phenol (paracetamol) and then alcohol (primary, secondary or tertiary) suc h a morphine. The transformation of the drugs involves a condensation reaction and hence release of water, while the conjugate replaces the hydrogen on the -OH group. Present in the ER uridine-5-diphosphae-alpha-D glucoronic acid is produced due to oxidation of carbon position six of UDP-ÃŽ ±-D-glucose. Interaction of this co factor with the substrates is catalysed by one the two classes of UGT1 or UGT 2, present mostly in liver however still found in brain and lungs. As this pathway produces a wide variety of procucts, work has been done to divide them into four groups of O/S/C/N glucoronides, with the o-glucoronides being the most important forming a reactive metabolite known as acyl-glucuronides. Generally drugs containing functional groups such as carboxylic acid, alcohol and phenol give rise more examples shown in fig 10. Acetylation Involving a transferring of an active acetyl linked via a thioester bridge to acetyl-coenzyme A (fig below) to a nucleophilic function group of substrate this metabolic pathway mainly occurs in liver involving amino groups of medium basic properties. One of the common drug metabolized by this pathway is the para-aminosalicly. Large group of enzymes known as acetyltransferase are enzymes involved in catalyzing this pathway, among these are the aromatic-hydroxylamine O-acetyltransferase and the arylamine N-acetyltransferase. Interestingly, genetic polymerization of acetylation function has meant that the rate of reaction and occurrence of toxicity will differ in accordance to the polymers. Fast acetylation will have result in a fast conversion and elimination while slow acetylators will have the opposite effect and will lead to build of unconjugated compounds in the blood and hence leading to toxicity. Conjugation with co-enzyme A Commonly using this pathway are the carboxylic containing which are activated into an Intermediate and eventually forming a acetyl-CoA conjugate It is important to note that primary metabolites from this reaction do not show up in vivo and only in vitro, however some of its secondary and stable metabolites that have undergone further reactions do. A factor that seems to cause problems with this pathway is the occurrence of toxicity, rare but serious as it the conjugates interfere with normal endogenous pathway. A common example was seen with NSAID which have now been long removed from market. Conjugation with amino acid This metabolic pathway is the most important for carboxcylic drugs where they form conjugate with the most common amino acid, glycine. Products are non-toxic (with no exception) and more water soluble than their parent compound. The drugs first become activated to the co- enzyme A before forming an amide or peptide bond between its carboxylic group and amino acid. The enzymes that facilitate this reaction are those of N-acyl transferases, such as glutamine N-acyltransferase. Carboxylic substrate for this pathway are also of an competition for the glucoronic conjugation, at high concentration if drugs glucoronic conjugation is preferred due to high availability, while at low concentration conjugation with amino acid is used for the metabolism. Conjugations with Glutathione Conjugation with glutathione has a wide variety of substrate specificity; this is partly due to the fact that in vivo glutathione exists as in equilibrium between its oxidised and reduced form hence enabling it to accept a wider range of substrate. The reduced form of glutathione is able to act as a protecting agent as it removes free radicals while the oxidised form oxidizes peroxides. A thiol, the glutathione contains a tripeptide and with a pka of 9.0, allowing it to be an excellent nucleophile agents, due to the increase in the ionization due to the thiol group. As the result of these electrophilic groups are easily attacked, usually on the most electrophilic carbon (commonly sp3 or sp2 hybridised) that contains the functional group. Enzymes responsible for catalyzing these reactions are known as glutathione transferase, seven of which are found in human. They also serve an important role apart from catalysing as upon binding of the active side with the glutathione will results i n a decrease in pka value and hence an increase in acidity (the thiol is deprotonated thiolate), thus enhancing the nucleophilic abilities. Depending on the substrate in question the conjugation with glutathione can be divided into forms, nucleophilic substation or nucleophilic addition. During the nucleophilic addition, an addition followed by an elimination reaction occurs. Attack occur at the activate electron lacking CH2 group, which the glutathione substitutes as it becomes added on to the carbonyl as shown in fig 12. Nucleophilic substitution reaction is much more common with xenobiotic than drugs although it is seen with chloramphenicol, where its -CHCL2 becomes electrophilic due to a electron withdrawing group. One of the most important conjugation in relation to glutathione is with epoxides giving rise to a protective mechanism of liver. The more chemically active epoxide undergo this reaction are attacked at carbon sp3 hybridised via nucleophilic addition. The metabolite will lose a water molecule via dehydration catalyzed by acid giving rise to a GSH aromatic conjugate. As a final metabolite a mercapturic acid (a condensation reaction exerted by urine) as shown in (fig below) is formed via a series reactions including cleavage and n-acetylation . 2.1 Metabolism in the liver When a drug can be cleaved by enzymes or biochemically transformed, this is referred to as drug metabolism. The main site of drug metabolism within the body occurs in the liver, however, this is not the only site in which metabolism of drugs occurs, this will be discussed later. The liver ensures drugs are subjected to attack by various metabolic enzymes; the main purpose of these enzymes is to convert a non-polar drug into more polar molecules, thereby increasing elimination via the kidneys. The polar molecules formed are known as metabolites, these lose a certain degree of activity compared to the original drug. Metabolic enzymes, cytochrome P450 enzymes enable the addition of a polar compound to particular drugs, making them now polar and more water-soluble. On the other hand, some drugs may become activated and then have the desired effect within the body, these are referred to as pro-drugs; and will be considered in greater detail later. Drug metabolism is split into two stages known as Phase I reaction and Phase II reaction, both of which have been discussed earlier. Certain oral drugs undergo a first pass effect in the liver, thereby reducing bioavailablity of the drug. This can lead to numerous problems, such as, individual variation that can then lead to unpredictable drug action, and a marked increase in metabolism of the drug. These problems related to the first pass effect may hinder the desired therapeutic effects from being fully achieved. Many drugs undergo first pass metabolism, previously seen as a disadvantage, but now due to a greater understanding of hepatic metabolism it can be used advantageously, for example Naproxcinod. Naproxcinod is related to naproxen, which will be discussed below, we will also be examining the metabolism of propanolol. Naproxcinod is derived from the non-steroidal anti-inflammatory drug (NSAID), Naproxen. First we will examine the metabolism of Naproxen (6-methoxy-a-methyl-2-naphthyl acetic acid). Naproxen is a widely used NSAID, possible of blocking both cyclo-oxygenase isoforms 1 and 2, therefore making it a non-selective inhibitor of these isoforms. Rheumatoid arthritis and osteoarthritis are the main reason for use of naproxen, which is administered orally as the S-enantiomer. This particular drug is well absorbed by the body and is metabolised in vivo to form various metabolites, the major metabolites being naproxen-b-1-O-acylglucuronide (naproxen-AGLU) and desmethyl-naproxen (DM-naproxen). Naproxen is conjugated in a Phase II reaction with glucuronic acid to form an acyl glucuronide (Diagram 2), with the intermediate being DM-naproxen. Usually conjugation reactions produce inactive metabolites, however with glucuronic acid the metabolite formed can occasionally become active. This reaction is facilitated by the superfamily UDP-glucuronosyl transferase (UGT) enzymes. The major UGT isoforms found in the liver are: 1A1, 1A3, 1A4, 1A6, 1A9, 2B4, 2B7 2B10, 2B15, 2B17 and 2B28. The isoform 2A1 is found mainly in the nasal epithelium, while 1A7, 1A8 and 1A10 are only localised to the gastro-intestinal tract. UGT acts as a catalyst enabling glucuronic acid to bind to naproxen at the carboxylic acid group via covalent bonding. It has been found that all UGT isoforms contribute to the conversion of naproxen to its metabolite naproxen-AGLU, except UGT-1A4, 2B4, 2B15, and 2B171. This reaction produces a highly polar glucuronic acid molecule bound to naproxen. Its main mode of elimination is through the urine. The next major metabolite of naproxen is, DM-naproxen. Demethylation of naproxen forms DM-naproxen, via removal of a single methyl group, as shown in Diagram 3. An unstable metabolite is formed during this process, however it is hydrolysed immediately to DM-naproxen. The enzymes involved in this reaction are cytochrome P450 1A2 and 2C9 from Phase I. Once DM-naproxen has formed it is glucuronidated with the help of UGT enzymes 1A1, 1A3, 1A6, 1A9 and 2B7 and converted to its acyl glucuronide. UGT-2B7 is a high affinity enzyme and so has a high activity in this process, as does UGT-1A6. UGT-1A4, 2B15 and 2B17 do not contribute to the acyl glucuronidation process1. DM-naproxen is also converted to phenolic glucuronide; this is formed by the UGT enzymes 1A1 and 1A9. Enzymes UGT 1A3, 1A6 and 2B7 appear to play no part in this reaction. UGT 2B7 works well in glucuronidating the carboxylic acid moiety in particular drugs; however it is unable to glucuronidate the phenolic group, so for this reason is not involved in forming phenolic glucuronide. The aim of hepatic metabolism is to ensure metabolites are made more water-soluble hence easily excreted. All metabolites formed from naproxen are water soluble and easily eliminated from the body. However, there are two metabolites that have been found to be far more water soluble, these are naproxen-AGLU and acyl glucuronide2. Huq (2006) explains this is due to the high solvation energy of both metabolites compared to naproxen and its other metabolites. Metabolites of Naproxen: Naproxen is a widely prescribed NSAID and works extraordinarily well; however there are several undesirable adverse effects, which precipitate after an extended period of use, such as increase in blood pressure. A new drug has been derived from naproxen without this effect, Naproxcinod. From Diagram 19 it is possible to see that the hydroge Processes of Drugs Metabolism in the Body Processes of Drugs Metabolism in the Body Abstract Metabolism of drugs is a complex and major process within the body, occurring primarily in the liver. The aim of metabolism is to make the drug more polar to enable excretion via the kidneys. The basic understanding of drug metabolism is paramount to ensure drug optimisation, maximum therapeutic benefits and a reduction in adverse effects. Essentially drug metabolism is broken down into two phases, Phase I and Phase II. Phase I is concerned with the biotransformation of compounds, and then transferred to Phase II. However, for some drugs this is the end of their metabolic journey in the body, as they produce more polar compounds which are readily excreted. Phase II reactions are where compounds are conjugated to produce more water soluble compounds for easy excretion. Phase I reactions are dominated by the Cytochrome-450 enzyme superfamily. These enzymes are found predominantly in the liver, which is the major site of drug metabolism. However, drug metabolism is not localised merely to the liver, there are other major sites at which this process occurs. Some of these sites include the skin, lungs, gastro-intestinal tract and the kidneys; close to all tissues have the ability to metabolise drugs due to the presence of metabolising enzymes. The most important enzymes are the cytomchrome-450 superfamily, which are abundant in most tissues. Inactive drugs with the ability to reconvert to the active parent drug once metabolised to exert their therapeutic actions are defined as prodrugs. They are classified depending on the site of conversion and actions (gastrio-intestinal fluids, intracellular tissues or blood). This report gives different study examples of such prodrugs and how their metabolism differs within the body, compared to their active metabolites. Individual drug metabolism may be affected by variant factors, such as, age or sex. Drug metabolism can cause an increase in toxcity. The bioactivation of a parent compound can form electrophiles that bind to proteins and DNA. Some of this toxicity can occur in Phase I metabolism e.g. acetaminophen. However, in some circumstances toxicity occurs in Phase II e.g. zomepirac, polymorphism can also cause idiosyncracity of certain drugs to be toxic. 1.1 Phase I Phase one, otherwise known as drug biotransformation pathway is generally broken into oxidation, reduction and hydrolysis. A reaction under this phase involves an addition of oxygen molecule aiming to improve the water solubility of drugs. As the result some metabolites from this phase can be extracted immediately if they are polar enough however at times a single addition of oxygen is not sufficient enough to overcome the lipophilicity of certain drugs and hence their metabolite from this phase has to be carried onto phase II for further reactions. Major example of Oxidation: Accounting for roughly 20 complex reactions the most important oxidative metabolic pathway dominating phase I is the cytochrome-P450 (CYP450) monooxygenase system processed by C-P450. Located primarily in the liver CYP450 was found to be present in all forms of organisms, including humans, plant and bacteria. It is important to note that the function of CYP450 goes beyond drug metabolism but it is also involved in metabolism of xenobiotics, fat soluble vitamin and synthesis of steroids. With substrate specificity of more than 1000 and its ability to produce activated metabolites such as epoxide are the underlying reason for its dominance and importance in drug discovery. The general mechanism the CYP450 monooxygenase oxidation is: R + O2 + NADPH + H+ à   ROH + H2O + NADP+ (fig 2) From the above formula it can be this reaction is of NADPH (Nicotinamide adenine dinucleotide phosphate) and an oxygen molecule dependent. As mentioned above oxygen is important to increase the water solubility and in the same manner NADPH is also important for oxygen activation and source of electron. Also important for activation of oxygen is the presence of cystine amino acid located near the protein terminal carboxyl of CYP450. Among the 500 amino acid present in CYP450, cystine has proven to be most important as it activates the oxygen to a greater extend. This is due to the fact that it contains a thiol group as one of its ligand and it is the thiol which alerts the reactivity. Highlighting the numerous intermediate structures involved as well as function of iron, oxygen and proton (Figure) shows the catalytic conversion required for cp450 oxidation reaction to place. The binding of the substrate with low spin ferric CYP450 enzyme induces a change in its active site. This will effects the stability of the water ligand and will displace it (shown in the diagram from a-b). Containing a high spin heme iron the enzyme and substrate form a ferric complex. The change in electronic state will result in the release and transfer of one electron from NADPH via electron transfer chain (reducing ferric heme iron to ferrous state) and thus reduction of the complex. The second electron is transferred when the complex reacts covalently with the oxygen forming a new ternanry complex. Initially the complex is an unstable oxy-P450(diagram d), however this is reduced to produce ferrous peroxide by a loss of an electron. This intermediate is short lived and undergoes protonati on twice resulting in a release one water molecule. Out of the oxygen molecules released one in incorporated in this water molecule and the remaining into the substrate. Another method of forming the iron-oxo intermediate is via the peroxide shunt which elimited steps from C to F. Some of the common addition of oxygen molecule reactions which CYP450 dependent are known as epoxidation (of double bond), N-hydroxylation, oxygen/nitrogen/ sulfur dealkylation, s-oxidation, dechlorination, oxidative desulfurisation and aromatic hydroxylation. Note they all follow the same principle of adding oxygen molecule to the substrate. The diagram below provides an example of how these reactions are processed: Aromatic hydroxylation substrate mostly produces phenols such as that seen on figure 3. The production of Phenol can be either via a non enzymatic rearrangement or by Epoxide hydrolase and cytosolic dehydrogenase which will ultimately give rise a catechol. The position of hydroxylation depends greatly on the nature of the R- group attached to the ring; an electron withdrawing group will position the -OH group on the metha while the electron donating will position it on the para or ortha. Aromatic hydroxylation also involves a change in NIH shift, which involves the movement and shifting of the R group to an adjacent position during the oxidation. It is important to note that certain substrate for aromatic hydroxylation can also be oxidized via the aliphatic (C-H) hydroxylation. Under such condition the aliphatic C-H) hydroxylation will oxidize it. Aliphatic dehydrogenation can also occur involving electron transfer to the CYP450. Currently more than 50 CYP-450 has been identified in human, however the bulk of drug metabolism is essentially carried by CYP1, CYP2 and CYP3 families, especially the CYP450-3A. The diagram on the right hand side clearly demonstrate just how much of drug metabolism is CYP450 3A responsibility in comparison to other, accounting for roughly 50%. Metabolism of drugs given orally are greatly determined by CYP450-3A primarily because this enzyme is present in both the liver and intestine and thus providing a barrier for all drugs before they can enter the systemic circulations, otherwise commonly known as ‘first pass effect. Upon entering the drugs are taken up via passive diffusion and/or facilitated diffusion or active transport into the entercocyte where they can be metabolized by CYP450-3A. They can once again be metabolized by the very same enzyme when they enter the liver (hepatocyte) ,which unlike the intestine in order to reach the systemic circulation it is unavoidable. Th is family of enzymes are also known to be cause of many serious adverse effects as they are influenced by diet and drug components, hence drug-drug and drug-food interactions is an important factor. Flavin monooxygenases Similar to cytochrome p450 monooxygenases system,Flavin monooxygenasesalso plays a major role in metabolism of drugs, carcinogens and Nitrogen/ sulfur/ phosphorous containing compounds. Also oxygen and NAPDH dependent, Flavin monooxygenases has much broader substrate specificity than CYP450. Once they have become associated with substrate the flavin monooxygenases is activated into 4ÃŽ ±-hyroperoxyflavin and unlike CYP450 the oxygen activation takes place without the need for substrate to bind to the intermediate. This pre-activated oxygen means that any compound binding to the intermediate is a substrate to be metabolized. The fact that this enzyme is able to remain stable and lacks any need for correct arrangement and disorientation of the substrate gives it ability to withhold all the energy required for the reaction to takes place and hence as soon as appropriate lipophilic substrate becomes available it starts the process immediately. Adverse side effects are rarely associated w ith these enzymes. The binding of oxygen to the reduced flavin is processed via a non-radical nucleophilic displacement. The substrate is oxidized via a nucleophilic attack by the oxygen that is located at end of 4ÃŽ ±-hyroperoxyflavin. This is then followed by cleavage of peroxide. The flavin monooxygenase catalytic cycle is finished once the original form of 4ÃŽ ±-hyroperoxyflavin has been regained using NADPH, oxygen and hydrogen proton. Note the metabolite product can at any times undergo reduction back to its original parent form. Alcohol dehydrogenase and aldehyde dehydrogenase These families of enzymes are both zinc containing NAD specific and catalyze the reversible oxidation of alcohol and aldehydes respectively. Grouped into 1-6 Alcohol dehydrogenase, are homodimer that exist in the soluble section of the tissue. It is involved in metabolism of some drugs such as cetirizine however it is more predominantly known as alcohol metabolism enzyme specifically ethanol, whether products of peroxides or that of exogenous (i.e administered drugs). It is important to note that although alcohol dehyrogenase is the main metabolic pathway for ethanol, however CYP2E1 also plays in its metabolism. CYP2E1 can be induced by ethanol resulting in adverse side effects between alcohol and with certain analgesics drugs. Alcohol dehydrogenase also metabolizes ethylene glycol and methanol. With a longer half life and rapid absorption from the gut, methanol can result in series of unpleasant side effects and metabolic acidosis, hence highlighting the importance of alcohol dehydr ogenase. Similarly, aldehyde dehydrogenase catalysis the oxidation of aldehyde to its corresponding carboxylic acid. Class one of alcohol dehydrogenase plays a major role in detoxification of anti cancer drugs. Alcohol dehydrogenase is also involved in reduction pathway of aldehyde or ketone back to its pharmacologically active alcohol form. Monoamine oxidase and diamine Located in liver, intestine and kidney as few of its site, this membrane bound enzyme is divided into two classes in accordance to their substrates specificity, they are monoamines-A and monoamine-B. Responsible for metabolizing amines via deamination to aldehyde, these enzymes are flavin containing enzymes and within their cysteinyl residue the flavin is linked to the covalently bounded flavin via a thioether. Monoamine oxidase has several substrates, ranging from secondary to tertiary amines that have alky group smaller than methyl. The general mechanism for this enzyme is the two electron oxidation shown below: R.CH2.NH2 + O2 + H2O à   R.CHO + NH3 + H2O2 (fig 7) As it can be seen this reaction requires oxygen to react and a hydrogen peroxide is produced as for every â€Å"one molecule of oxygen is absorbed for every molecule of substrate oxidized† (Principle of drug metabolism, 2007). Proportional to the rate of oxygen uptake this is commonly used to deduce the rate of reaction. Research has shown that monoamines-A is more commonly involved in oxidation of endogenous substrates such as noradrenalin while monoamine-B which is found mostly in platelets appears to catalyses exogenous substrates such as phenylethylamines. Their common substrate is dopamine. Inhibition of monoamine oxidase has long been of an interest for scientist in treatment of several of illness such as depression. Present in liver, lungs and kidney as few of its locations diamine oxidase also catalyses the formation of aldehyde from histamine and diamines in the same manner. Reduction This pathway of metabolism is enzymatically the least studied in phase I and yet it plays an important role in metabolism of disulfides and double bonds of for example progestational steroids as well as dehydroxylation of aliphatic and aromatic compounds. In general ketone containing xenobiotics are more readily metabolized and eliminated via this pathway in the mammalian tissue. This is due to the fact that the carbonyl group is very lipophilic, thus the lipophilicity will be reduced and elimination is ensured as ketone is converted to alcohol. One of the major enzymes involved in this pathway is the NADPH cytochrome P450 reductase. Containing flavin adenine dinucleotide and flavin mononucleotide is an electron donor playing an important role in the metabolism of drugs such as chloramphenicol by reducing its nitro group. Hydrolysis As the name suggests this pathway uses water to cause a breakage of a bond. Major enzymes under this pathway are the amide and ester hydrolysis and hence amide and esters are the common substrates. Naturally esters are much easier targets to esterase hydrolysis than amides. A very common amide substrate is a local anesthetic, Lidocaine and an antiepileptic drug known as levetiracetam. Catalyzing ester and certain type of amides are the group of enzymes referred to as carboxylesterase. This enzyme hydrolysis choline like ester substrate and procaine. As a rule, the more lipophilic the amide the better it be accepted as a substrate for this enzyme and thus eliminated. Esters that are sterically hindered are however much harder and slower to be hydrolysed and will usually be eliminated unchanged at a high percentage such as that for atropine, eliminated 50% unchanged. A very good example of esterase enzyme is the paraoxonase. The hydrolysis of substrate such as phenyl acetate and other acyl esters are catalyzed by this. For hydrolases and substrate to be involved in this pathway certain criterias are imperative for a fast reaction rate, these include having a electrophilic group a nucleophile that will attack the carbon attached to the oxygen resulting in a formation of tetrahedral orientation. The presence of a hydrogen donor to the improvers the leaving group abilities is the final requirement. 1.2 Phase II (Second part of drug metabolism): Second part of drug metabolism, involves introduinh of new ionic chemicals on to the substrate (including the metabolites from phase I) in order to increase its water solubilyt for elimination. This phase is usually refered to as conjugation reaction and its products are generally inactive unlike those of phase 1. The following reaction are major conjugation of phase II. Methylation is the transfer of methyl group to the substrate from cofactor s-adenosyl-L-methionine (fig 9). S-adenosyl-L-methione is an active intermediate that receives a transferred methyl group from methionine after its linkage with ATP in presence of adenosine transferase enzyme. It is this methyl group that is ultimately transferred on to the substrate. S-adenosyl-L-methionine methyl group becomes attached to the sulfonium center marking â€Å"electrophilic character† (Principle of drug metabolism, 2007). Depending on the functional group present on the substrate Conjugation via methylation is broken down to nitrogen, oxygen and sulfate methylation. O-methylation O-merthylation is the most common reaction that occurs for substarte containing the organic (formally known as pyrocatechol compound, catechol moiety) hence why the enzyme responsible for this type of reaction is called catechol O-methyltransferase. This Magnesium dependent, found cyclic but also, less frequently, as a membrane bound enzyme, is found commonly in liver and kidney among other tissues. Common drug for this type reaction are L-DOPA, where generally the methyl is transferred on to the substrate in meta position and less commonly para, depending the substituent (R group) that is attached on the ring. According to ‘Principle of drug metabolism the rate of reactivity of O-methylation is decreased in accordance to size of the substituted group, the larger it is the slower the rate of reaction degree of acidity of the catechol group itself. N-methylation Naturally this reaction has substrate specificity of amine, involving however primary and seconday only. Unlike the above reaction, N-methylation consists of several enzymes, all of which are categorized in accordance to the specific type of amine substrate which they catalyze. Enzymes such as amine-N-Methyltransferase, nicotinamide-N-methyltransferase and histamine-N-methyltransferase are few examples. Despite the substrate specificity all the enzymes involved do however follow the same principle of transferring methyl fromcofactor s-adenosyl-L-methionine to the substrate. With drug substrates such as captoril, reactions of N-methylation can be broken down into two distinct types as illustrated in Fig 11. Reactions that have a low pharmacological significant yield an ineffective n-methylation as the substrate and the product have a same electrical state thus the metabolites are usually less hydrophilic than parent. As it can be seen from fig 7a, in these reactions one proton is exchange for a methyl group. On the other hand a more hydrophilic product and an effective reaction of detoxification is achieved with pyridine type (nitrogen atom) substrate. These substrate will result in a creation of positive change on the product (fig 7b) rather than an exchange process. Sulfate and phosphate conjugation Sulphate conjugation is one of the most important reactions in biotransformation of steroids, effecting its biological activates and decreasing its ability for its receptor. Nucleophilic hydroxyl groups such as alcohol and phenol, primary or seconday amine and drug containing a SO-3 group are the common substrates for this pathway. Generally sulphate are transferred via a membrane bound enzyme named sulfotransferase (located in golgi apparatus) from their cyclic cofactor 3-phosphoadenosine 5 (shown in fig 8 ) to substrate. 3-phosphoadenosine 5 is formed in a reaction between adenosine triphosphate and inorganic sulfate where the sulfate/phosphate group are bonded via a anhydride linkage which gives rise an exothermic reaction when broken, hence providing the energy for the reaction. In human there is two class, SULT 1A- 1E and SULT 2A-2B, each of which will have different specificity yet with overlaps. This enzyme acts on both endogenous as well as exogenous compounds as long as they possess an alcohol (less affinity with varying product stabilities) or phenol (products are stable arly sulfate esters with a high affinity). Substrates are generally of medium sized, highly ionized and hydrophilic, hence excreted easier via urine. The rate of this pathway is determined by the lipophilicity and nature of amino acid present on the substrate. Interestingly phenol is also of an interest for the Glucoronic conjugation pathway and are metabolized by this when they are at high concentration and 3-phosphoadenosine 5 becomes rate limiting. The sulfate conjugation will produce ester sulfate or sulfamide some of which will undergo further heterolytic reaction leading to electrophilic substrate and hence toxicity. Unlike the sulfate conjugation the phosphate conjugation is less common unless the drug in question is anticancer or antiviral. Catalyzed phosphotransferases. conjugation The most important and major occurring metabolic pathway of phase II is the glucoronic conjugation, accounting for the largest share of conjugated metabolite in the urine. This pathway is important due to the fact there is a high availability of glucucronic acid, huge substrate specificity and the wide range of poorly reabsorbed metabolite. The glucoronic conjugation takes place as the glucoronic acid is transferred to the acceptor molecule from its cofactor uridine-5-diphosphh-alpha-glucoronic acid (fig 9 ) of which glucoroniuc acid is attached in 1 ÃŽ ± configuration. However products produced are in ÃŽ ²-configuartion. This is due to the nucleophilicity of the functional groups of the substrate. To be able to undergo this pathway of metabolism the functional group of drugs in question must have nucleophilic characteristics. Generally the drug that are at high affinity for this pathway is firstly phenol (paracetamol) and then alcohol (primary, secondary or tertiary) suc h a morphine. The transformation of the drugs involves a condensation reaction and hence release of water, while the conjugate replaces the hydrogen on the -OH group. Present in the ER uridine-5-diphosphae-alpha-D glucoronic acid is produced due to oxidation of carbon position six of UDP-ÃŽ ±-D-glucose. Interaction of this co factor with the substrates is catalysed by one the two classes of UGT1 or UGT 2, present mostly in liver however still found in brain and lungs. As this pathway produces a wide variety of procucts, work has been done to divide them into four groups of O/S/C/N glucoronides, with the o-glucoronides being the most important forming a reactive metabolite known as acyl-glucuronides. Generally drugs containing functional groups such as carboxylic acid, alcohol and phenol give rise more examples shown in fig 10. Acetylation Involving a transferring of an active acetyl linked via a thioester bridge to acetyl-coenzyme A (fig below) to a nucleophilic function group of substrate this metabolic pathway mainly occurs in liver involving amino groups of medium basic properties. One of the common drug metabolized by this pathway is the para-aminosalicly. Large group of enzymes known as acetyltransferase are enzymes involved in catalyzing this pathway, among these are the aromatic-hydroxylamine O-acetyltransferase and the arylamine N-acetyltransferase. Interestingly, genetic polymerization of acetylation function has meant that the rate of reaction and occurrence of toxicity will differ in accordance to the polymers. Fast acetylation will have result in a fast conversion and elimination while slow acetylators will have the opposite effect and will lead to build of unconjugated compounds in the blood and hence leading to toxicity. Conjugation with co-enzyme A Commonly using this pathway are the carboxylic containing which are activated into an Intermediate and eventually forming a acetyl-CoA conjugate It is important to note that primary metabolites from this reaction do not show up in vivo and only in vitro, however some of its secondary and stable metabolites that have undergone further reactions do. A factor that seems to cause problems with this pathway is the occurrence of toxicity, rare but serious as it the conjugates interfere with normal endogenous pathway. A common example was seen with NSAID which have now been long removed from market. Conjugation with amino acid This metabolic pathway is the most important for carboxcylic drugs where they form conjugate with the most common amino acid, glycine. Products are non-toxic (with no exception) and more water soluble than their parent compound. The drugs first become activated to the co- enzyme A before forming an amide or peptide bond between its carboxylic group and amino acid. The enzymes that facilitate this reaction are those of N-acyl transferases, such as glutamine N-acyltransferase. Carboxylic substrate for this pathway are also of an competition for the glucoronic conjugation, at high concentration if drugs glucoronic conjugation is preferred due to high availability, while at low concentration conjugation with amino acid is used for the metabolism. Conjugations with Glutathione Conjugation with glutathione has a wide variety of substrate specificity; this is partly due to the fact that in vivo glutathione exists as in equilibrium between its oxidised and reduced form hence enabling it to accept a wider range of substrate. The reduced form of glutathione is able to act as a protecting agent as it removes free radicals while the oxidised form oxidizes peroxides. A thiol, the glutathione contains a tripeptide and with a pka of 9.0, allowing it to be an excellent nucleophile agents, due to the increase in the ionization due to the thiol group. As the result of these electrophilic groups are easily attacked, usually on the most electrophilic carbon (commonly sp3 or sp2 hybridised) that contains the functional group. Enzymes responsible for catalyzing these reactions are known as glutathione transferase, seven of which are found in human. They also serve an important role apart from catalysing as upon binding of the active side with the glutathione will results i n a decrease in pka value and hence an increase in acidity (the thiol is deprotonated thiolate), thus enhancing the nucleophilic abilities. Depending on the substrate in question the conjugation with glutathione can be divided into forms, nucleophilic substation or nucleophilic addition. During the nucleophilic addition, an addition followed by an elimination reaction occurs. Attack occur at the activate electron lacking CH2 group, which the glutathione substitutes as it becomes added on to the carbonyl as shown in fig 12. Nucleophilic substitution reaction is much more common with xenobiotic than drugs although it is seen with chloramphenicol, where its -CHCL2 becomes electrophilic due to a electron withdrawing group. One of the most important conjugation in relation to glutathione is with epoxides giving rise to a protective mechanism of liver. The more chemically active epoxide undergo this reaction are attacked at carbon sp3 hybridised via nucleophilic addition. The metabolite will lose a water molecule via dehydration catalyzed by acid giving rise to a GSH aromatic conjugate. As a final metabolite a mercapturic acid (a condensation reaction exerted by urine) as shown in (fig below) is formed via a series reactions including cleavage and n-acetylation . 2.1 Metabolism in the liver When a drug can be cleaved by enzymes or biochemically transformed, this is referred to as drug metabolism. The main site of drug metabolism within the body occurs in the liver, however, this is not the only site in which metabolism of drugs occurs, this will be discussed later. The liver ensures drugs are subjected to attack by various metabolic enzymes; the main purpose of these enzymes is to convert a non-polar drug into more polar molecules, thereby increasing elimination via the kidneys. The polar molecules formed are known as metabolites, these lose a certain degree of activity compared to the original drug. Metabolic enzymes, cytochrome P450 enzymes enable the addition of a polar compound to particular drugs, making them now polar and more water-soluble. On the other hand, some drugs may become activated and then have the desired effect within the body, these are referred to as pro-drugs; and will be considered in greater detail later. Drug metabolism is split into two stages known as Phase I reaction and Phase II reaction, both of which have been discussed earlier. Certain oral drugs undergo a first pass effect in the liver, thereby reducing bioavailablity of the drug. This can lead to numerous problems, such as, individual variation that can then lead to unpredictable drug action, and a marked increase in metabolism of the drug. These problems related to the first pass effect may hinder the desired therapeutic effects from being fully achieved. Many drugs undergo first pass metabolism, previously seen as a disadvantage, but now due to a greater understanding of hepatic metabolism it can be used advantageously, for example Naproxcinod. Naproxcinod is related to naproxen, which will be discussed below, we will also be examining the metabolism of propanolol. Naproxcinod is derived from the non-steroidal anti-inflammatory drug (NSAID), Naproxen. First we will examine the metabolism of Naproxen (6-methoxy-a-methyl-2-naphthyl acetic acid). Naproxen is a widely used NSAID, possible of blocking both cyclo-oxygenase isoforms 1 and 2, therefore making it a non-selective inhibitor of these isoforms. Rheumatoid arthritis and osteoarthritis are the main reason for use of naproxen, which is administered orally as the S-enantiomer. This particular drug is well absorbed by the body and is metabolised in vivo to form various metabolites, the major metabolites being naproxen-b-1-O-acylglucuronide (naproxen-AGLU) and desmethyl-naproxen (DM-naproxen). Naproxen is conjugated in a Phase II reaction with glucuronic acid to form an acyl glucuronide (Diagram 2), with the intermediate being DM-naproxen. Usually conjugation reactions produce inactive metabolites, however with glucuronic acid the metabolite formed can occasionally become active. This reaction is facilitated by the superfamily UDP-glucuronosyl transferase (UGT) enzymes. The major UGT isoforms found in the liver are: 1A1, 1A3, 1A4, 1A6, 1A9, 2B4, 2B7 2B10, 2B15, 2B17 and 2B28. The isoform 2A1 is found mainly in the nasal epithelium, while 1A7, 1A8 and 1A10 are only localised to the gastro-intestinal tract. UGT acts as a catalyst enabling glucuronic acid to bind to naproxen at the carboxylic acid group via covalent bonding. It has been found that all UGT isoforms contribute to the conversion of naproxen to its metabolite naproxen-AGLU, except UGT-1A4, 2B4, 2B15, and 2B171. This reaction produces a highly polar glucuronic acid molecule bound to naproxen. Its main mode of elimination is through the urine. The next major metabolite of naproxen is, DM-naproxen. Demethylation of naproxen forms DM-naproxen, via removal of a single methyl group, as shown in Diagram 3. An unstable metabolite is formed during this process, however it is hydrolysed immediately to DM-naproxen. The enzymes involved in this reaction are cytochrome P450 1A2 and 2C9 from Phase I. Once DM-naproxen has formed it is glucuronidated with the help of UGT enzymes 1A1, 1A3, 1A6, 1A9 and 2B7 and converted to its acyl glucuronide. UGT-2B7 is a high affinity enzyme and so has a high activity in this process, as does UGT-1A6. UGT-1A4, 2B15 and 2B17 do not contribute to the acyl glucuronidation process1. DM-naproxen is also converted to phenolic glucuronide; this is formed by the UGT enzymes 1A1 and 1A9. Enzymes UGT 1A3, 1A6 and 2B7 appear to play no part in this reaction. UGT 2B7 works well in glucuronidating the carboxylic acid moiety in particular drugs; however it is unable to glucuronidate the phenolic group, so for this reason is not involved in forming phenolic glucuronide. The aim of hepatic metabolism is to ensure metabolites are made more water-soluble hence easily excreted. All metabolites formed from naproxen are water soluble and easily eliminated from the body. However, there are two metabolites that have been found to be far more water soluble, these are naproxen-AGLU and acyl glucuronide2. Huq (2006) explains this is due to the high solvation energy of both metabolites compared to naproxen and its other metabolites. Metabolites of Naproxen: Naproxen is a widely prescribed NSAID and works extraordinarily well; however there are several undesirable adverse effects, which precipitate after an extended period of use, such as increase in blood pressure. A new drug has been derived from naproxen without this effect, Naproxcinod. From Diagram 19 it is possible to see that the hydroge