Misanthrope’s Satire

?Sarah Newsome 3-19-10 2nd Period Misanthrope Response The gossip session Moliere reveals in The Misanthrope among Acaste, Clitandre, and Celimene is that of a double satire. This conversation exemplifies Moliere’s satirical attitude towards the hypocrisy of individuals as well as a society which accepts, even forces, such falsehoods. He is equally critical of Alcaste’s impliant rectitude as he is of the other characters’ sense of falsehood. However, Moliere’s greatest satire focuses on the society which instigates both extremes as he carefully crafts each character and their dialogue. Moliere develops the characters of Philante and Eliante with the perfect balance of honesty and forgiveness so the satirical focus is on the corrupt society rather than the characters. Philante’s character is one of exculpation and acceptance, especially involving his fellow men and his selfless friendship with Alceste. Nonetheless, he is not afraid to suggest the idea of moderation when speaking the brutal truth as he stands up to Alceste by saying. â€Å"†¦you have a way of bridling at whatever people say; whether they praise of blame, your angry spirit is equally unsatisfied to hear it. † Similarly, the observant Eliante notices the nature of Celimene as a -gossip queen and even comments on it aloud when she says to Philante, â€Å"The conversation takes it’s usual turn, and all our dear friends’ ears will shortly burn. In such a simple sentence Moliere is able to speak through Eliante and Philante to express his condemnation of Celimene, Acaste, and Clitandre by admitting that dishonestly is constructed and accepted by society. Additionally, Moliere satirizes society by speaking through them in order to recognize that while not all people are hypocrites, society is the greatest threat as it accepts the false hypocrisies that do exist. Without the encouragement of suitors such as Acaste and Clitandre, Celimene would have less reason to degrade others. Likewise, without a society so accepting of falsehoods, Alceste would have less reason to be so cynical and disapproving of humanity. Therefore, although Moliere is equally critical of Acaste’s impliant rectitude as he is of the other characters’ dominating acceptance of untruth, the author’s greatest amount of satire is focused on the society when compels both extremes.

Panera Bread Company Essay

Executive Summary This report focuses on what Panera Bread Company (PBC) needs to do in order to be profitable, provide healthy and quality foods to consumers and above all retain its leadership potentials in the restaurant and fast food business. The report also looks at what organization’s vision and mission statement means. It touches strategic objectives by dealing with strategy formulation, analysis and implementation. Corporate governance has to be used to reposition the operations of PBC, analysis of both the micro and macro environmental points of view of the organization – where demographic, socio-cultural, political/legal, technological and global considerations of the organization in question. It also dwells on strength, weaknesses, opportunities and threats including studying trend analysis of the organization. Porter’s five forces model, concept of strategy groupings, resource based view, triple bottom line reporting, value chain analysis and financial analysis would have to be examined critically so as to make PBC have competitive advantage over its rivals. Based on the above concepts in this report, it is hereby recommended that PBC has to:†¢open new markets and establish branches in other countries by targeting major cities and towns using same standards, quality, menu, site selection and construction. †¢develop more healthy and quality foods, unique brands, always be ahead of competitors and try to use trend analysis to know the lifestyles of people, tastes, maintain its corporate social responsibility with stakeholders, look at marketing mix, develop its technological base and have a friendly atmosphere at their various cafes including motivating employeesIf these recommendations are implemented, it is believed that PBC will occupy more than 30% of the market share within the next few years. 1.Introduction1.1The aims of the report†¢how PBC can reposition its leadership edge by ensuring the management concepts remains special, opening up franchises, encourage transparencies in management practices and be  proactive in terms of change and innovations. †¢how PBC can sustain its rising profit and growth levels. 1.2Objective of the report†¢how PBC can ensure consistency in their vision, mission and strategic objectives by using major processes like strategy analysis, strategy formulation, implementation and corporate governance†¢Analyzing the micro and micro environments of PBC †¢Using Porter’s five forces model and concept of strategy groupings to make PBC have competitive advantage over their competitors. †¢Using resource base view and value-chain analysis to identify possible opportunities and threats for PBC. 2.Background of the CompanyPBC is a market leader in the restaurant industry business. Started business in 1981 with three bakery cafes and by 1997, their bakery cafes were 160 with branches in five countries and cafes in domestic airports and hotels. PBC’s concept is to sell only fresh dough and no preservatives. Their mission is ‘a loaf of bread in every arm’ with 18 different products. It intends to establish Wi-Fi access in 2003, and has many awards in its kitty. They have a good distribution network, franchise operations, management information system and supply chain management and highly professionalized staff. The 2004 first quarter performance showed an increase of 26% over same period in 2003 with a highly priced shares. 3.Case Study AnalysisStrategies are set of actions that firms use to achieve its goal. While strategic management focuses where an organization is at present and where it intends to be in the future. The task of analyzing a firm’s internal and external environment and selecting an appropriate strategy is known as strategy formulation. Strategy implementation involves  putting appropriate controls and organization mechanisms to keep the company’s chosen strategy into action. Vision statement is the long run aspirations of the organization while mission statement means what is expected of the organization by its stakeholders. This report focuses on micro-macro environment of PBC in order to retain their leadership role, increase market share and profitability. Resource Based View, Porters five forces model, strategic groupings, value chain, SWOT and financial analysis including triple bottom line reporting, and how these concepts would help the PBC to be a market leader would be analysed. 3.1Macro EnvironmentMacro economic factors are political, socio-cultural, environmental, economic, technological and legal. 3.1.1Political considerationPBC has to maintain its corporate governance issue by making sure that taxes are paid promptly and study government policies as it affects the business. At the moment political consideration is not really a big issue with PBC but if it intends to expand its operations, government polices of countries it wants to do business would have to be examined to see if it is business friendly or not. 3.1.2Demographic forcesAreas that are less profitable by the organizations should be closed down and move to areas that increases profitability (Hill et al 2004). Presently there is significant growth for young people and children who rarely cook at home and they patronize these fast casual restaurants. These youths are concerned about their health by eating healthy and quality foods which PBC should target for high profitability. 3.1.3Socio-cultural factorsIncreases in the population of women in workplaces are massive and higher levels of health consciousness have created a boom to many industries (Campbell et al 2006). PBC should study population demographics, income distribution and lifestyles changes within their areas of operation to their advantage. 3.1.4EnvironmentalOperating environments have to be friendly. This should  done in such a way that corporate social responsibility to communities in terms of pollution, waste disposal and environmental protection laws are adhered to (Johnson et al 2005). At the moment it runs ‘Operation Dough Nation’ where all monies received and all unsold inventories goes back to the community it operates. 3.1.5Economic factorsAlmost all the industries are prone to general economic conditions. High interest and exchange rates, and average disposal income can affect organizations to larger extent (Campbell et al 2006). At the moment business is booming for PBC, therefore it has to consider business cycles, product trends, interest rates, inflation and also disposable income of consumers in order to have a competitive edge. 3.1.6TechnologicalThis is now a global phenomenon in virtually every business. For a company to remain competitive it has to enhance its technological base to compete with rivals (Campbell et al 2006). PBC is expanding its technological base by introducing point of sale machines and credit cards network at each cafà ©. This helps in planning for marketing information, product mix, quicker accounting information and other variance analysis. 3.1.7LegalJohnson et al (2005) pointed out that organizations should be cautious of health and product safeties, employment laws and legislations. Taken into account its franchise operations with other organizations, it has to make sure that organizations’ it enters into agreements comply with its standards, quality, menu, site selection and construction of cafes. The training program organized by the organization prior to franchisee starting business is applauded. 3.1.8GlobalChanges in the environment such as political and economic have created a business boom to some countries, while some have witnessed economic recession as a result of this. Government policies and changing cultural patterns by consumers have had a positive impact in some industries while some are unhappy with these changes (Hill et al 2004). PBC should study these changes and know those ones that affect their business  especially intra-country trades where they have to convert currencies of their branch companies overseas. 3.2SWOT AnalysisThis shows the internal strengths and weaknesses of an organization from the customers’ point of view as they relate to external opportunities and threats (Hannagan 2002). 3.2.1StrengthStrengths of organizations are the committed leadership zeal of managers, experience in the industry, clear and articulate line with external stakeholders, strong product design and commitment to consumers in the area of innovation (Lee et al 1999). The strengths or core competencies PBC has at the moment over its competitors include the product, distribution and franchising, operations, marketing mix, general managerial ability and low personnel turnover. 3.2.2WeaknessesThese can be in the form of no clear management styles, poor image, research and development issue, competitive disadvantage, poor track record, insider problems, financing problems and possible training problems by managers and supervisors (Dess et al 2007). PBC has to invest in research and development, improve its image with stakeholders and improve on its marketing strategies. 3.2.3OpportunitiesThe growing demand for healthy and quality foods is an opportunity that PBC has at the moment over its competitors and it has to be sustained to make them have continuous dominant role in this industry (Stead et al 2004). Managers of PBC should analyse competitive forces in the restaurant sector in order to identify the various opportunities in terms of product enhancement and new products, create new markets and prediction of trends. 3.2.4Threats:What makes an organization to be strong is to identify possible threats within its operational base. The threats could be in the form of government policies, research, competitive pressures, new entrants, changing customers tastes, adverse demographic changes, recession, growing bargaining power of suppliers and customers (Dess et al 2007). PBC has to lay  particular emphasis on new entrants, watch industry indicators, government adverse policies and changes in customers needs and tastes. 3.3Resource based viewThis considers the opportunities available to a company either to add value to its products and services or look at ways of reducing costs (Dess et al 2007). It may be possible to add value to the value chain of an organization in terms of procurement of raw materials and production processes. The present system that PBC is using where it has signed agreement with Dawn Food Products and also having economic of scale in terms of supplies makes the pricing of their product very competitive. 3.4Porter’s five force industry competitionPorter’s five force industry competition include the threat of new entrants, the bargaining power of suppliers, the degree of rivalry among competitors in the same industry, the bargaining power of buyers and the threats of substitutes products. Porter argues that the stronger these forces are within an industrial setting the more limited companies raise prices and earn greater profits (Campbell 2006). As far as this is concerned a strong competitive force can be regarded as a threat because it would drastically reduce the profit of an organization (Williamson 2004). 3.4.1The threat of substitute productFirms within the same industrial setting are competing amongst themselves. Substitutes limits potential returns on an industry by placing a ceiling on the prices companies charge. This should be a lot of concern for PBC because there are lots of organizations offering same product in the market. 3.4.2The threat of new entrantsWhen new entrants enter the industry they tend to take extra effort in order to take full control of the industry. The extent to which new entrants can enter an industry exerts a significant influence on the degree to which companies may act to earn above average in terms of bottom line (Johnson et al 2005). At the moment PBC enjoys some element of economies of scale, brand recognition, access to distribution channels and experience in carrying out operational activities leading to lower cost of production. But it is good for new entrants to enter the  market because this brings about competition in the industry. 3.4.3The power of buyersBuyers are seen as competitive threats when they are in a position to demand lower prices or better service . Conversely when buyers are weak, a company can raise its prices and declare higher profits (Johnson and Scholes 2002). This has to be taken into account by PBC following volume of restaurants around. PBC should recalculate its costs since it intends to increase prices by 2% to see the justification prior to embarking on it. 3.4.4The power of suppliersSuppliers can be viewed as threats when they are able to force up the price for raw materials or reduce quality of materials. However, if suppliers are weak, companies can force down their prices and demand higher raw material quality. PBC believes it can have cost savings from switching to Dawn. 3.4.5Rivalry among established companiesIf rivalry is weak this will result to increase in prices of products at the detriment of consumers and ultimately increase profits and vise versa (Johnson 2005). PBC should regularly study competitors’ moves. 3.5.Value Chain Analysis (VCA)VCA helps managers to understand how effectively and efficiently the activities of their organizations are structured and coordinated. In other words, it seeks to provide an understanding of how much value an organization’s activities add to its products and services compared to the costs of the services used in their production. This helps management to identify core activities, know if there is breakdown or blockages to their detriment (Tsai et al 2006). The distribution network of PBC is good since it uses an independent contractor that delivers products to the bakery cafes and thus making the organization to concentrate in the retail operations. Their franchise operations should be sustained. 3.6Strategic groupsPotter (1980) defined strategic (SG) groups as group of firms in the same line of business having identical strategy following  through the strategic direction. Carroll et al (1992) as cited in Flavian and Polo (1999) organizations within the same SGs often compete for market share. PBC has a lot of organizations within the same SGs, and therefore should use this to their advantage by understudying their competitors strengths and weaknesses. 3.7Tripple bottom lineThis is the combination of social, environmental and financial reporting for an organization to its stakeholders (Dess et al 2006). PBC does not show its report in this format, although this is optional for organizations but to enable stakeholders understand PBC’s business better they should incorporate this into their report like the Operation Dough Nation and the unsold inventory proceeds. 4Recommendation†¢Encourage research for new products and branding. †¢Explore the possibility of new branches across borders. †¢Improve marketing drive to increase sales since its closing inventory in 2003 was $8066 million dollars as against $5191 million dollars in 2002. †¢Identify threats and weaknesses through strategic groupings†¢Pursue recovery of debts from debtors which shows $9646 million in 2003. Reduce its liabilities which gave $35,552 million dollars. †¢Plan for succession incase of possible changes in leadership hierarchy. 5.ConclusionIn conclusion, PBC should regularly scan the micro and macro environments for signals of environmental changes or general trends that are occurring. On observing a trend that may lead to a market changes, the company needs to monitor the change so it has a better understanding of the exact nature of the change and whether it applies to the organization. If the monitoring mechanism suggests the change is relevant, then the company needs to forecast how the change will affect its operations in future. It is then necessary to assess the forecast implications to determine whether the market change will require a change in the company’s strategy. Benchmarking,  reengineering and total quality management should not be left out. . References Dess, GG, Lumpkin, GT, Eisner, AB 2007, ‘Strategic management’ , 3rd edn, McGraw-Hill, New York. Campbell, D, Stonehouse, G, Houston, B 2006, ‘Business strategy’, 2nd edn, Elsevier Butterworth-Heeinemann, Oxford. Stead, EW, Stead, GJ, Starik, M 2004 ‘Sustainable strategic management’, M.E. SharpeInc., New York. Tsai, YC, Fan, CL, Liou, CN, Wu, CL 2006 ‘The application of parts control and standardization by exploration of the value chain in new product development and innovation’, The Business Review, vol. 6, no. 2, pp 213 (online Emerald). Hanaagan, T 2002 ‘Mastering strategic management’, Palgrave, New York. Hill, CWL, Jones, GR, Galvin, P 2004, ‘Strategic management: an integrated approach’, 5th edn., John Wiley, Milton. Johnson, G, Schooles, K, Whittington, R 2005, ‘Exploring corporate strategy’, 7th edn, Prentice Hall, Harlow. Williamson, D, Jenkin, W, Cooke, P, Moreton, KM 2004, ‘Strategic management and business analysis’, Elsevier Butterworth-Heinemann, Burlington. Johnson, G, Scholes, K 2002, ‘Exploring corporate strategy’, 6th edn., Prentice Hall, Harlow. Porter, ME 1980, ‘Competitive strategy’, The Free Press, New York

Intercultural Communication Essay

There is always the existence of power in the society when people communicate, although it might not be evidently observed. At most instances, communication is assumed to take place between equal people, but this might not always be the case. There are basically different types of hierarchy that exists in the society which makes some people to be more powerful than others. This is a communication that takes place in intercultural communication. Those who are powerful either knowingly or unknowingly creates an environment that makes their communication more profound, hence asserting their authority over the others. People can be found in one communication group due to involuntary or voluntary cases. Involuntary occurs for instance when a person is of a certain gender, race, ethnic group, age and physical ability. The voluntary orientation occurs because of education background, geographic location, marital status, and socio-economic status. Basically those in the dominant group of communication usually impede those who are not in the same category with them. The most powerful in the society in terms of communication are usually also more privileged when it comes to many issues. There are some power relations that are usually rigid than others. For instance, power that occurs between gender is more rigid in changing than power that occurs for instance in a relationship between a student and a teacher. There are however many complication that can occur in intercultural communication due to the barriers that exists. The minority have been mostly powerless in communication compared with the other groups in the society. Basically the whites have always believed to be superior over many minority groups, especially the blacks. This is being ethnocentric. Many developed countries have looked down upon the less developed countries especially from Africa as they believe that the people from these countries can not be equated with them. The blacks whether immigrants or those who were born in the developed countries thus continue to be seen as less important people in the society, hence can not even be listened to, or be given an opportunity to prove their prowess in any arena by the whites. The white race believes to be the most dominant race than all the other races, hence undermining the rest. Many of the black people are also stereotyped in the American society. Many blacks can be found to be imprisoned more than the whites, yet in essence, it can not be said that the blacks are the ones who commit crimes more than the whites. But because of stereotypes, they are just considered to be naturally criminals. Any black seen walking around the white dominated area is usually looked at as a person who is bound to commit a crime even if a person has got no such intentions. This can occur because of generalizing issues that blacks are criminals, yet the whites commit crimes just as the blacks. In fact, because of stereotypes, the black suspect is more likely to receive punishment or a harsher punishment than a white suspect charged with the same offence. In most cases, stereotypes occur in unconscious manner, thus the only way to overcome it is by having a conscious way of avoiding it. In many white homes, children might grow up hearing the N word often used by their parents against the black people, hence the children also grow up with the same stereotypic nature the elders have over the blacks. Because of stereotype and prejudice that is rampant in the society against the blacks, they usually find themselves victims of discrimination. The blacks have been discriminated over many issues in the society ranging from political, social, and economic perspectives. In many instances, the blacks have been denied equal opportunity in the society by the more powerful whites. Discrimination can be exhibited in various forms that include subtle non verbal to verbal insults. Because of prejudice and stereotyping the less powerful people find themselves being even eliminated in the society through various means that can include genocide. This is a very mild form of discrimination. Discrimination can be at interpersonal or institutional level. Although there are nowadays less cases of interpersonal discrimination, the institutional level discrimination are still very high. At institutional level, the blacks are usually denied equal representation in different institutions in the society compared to their white counterparts. As already explained, the blacks usually find themselves at the wrong hand of the law more than the whites, not because the blacks commit crimes than whites, but because the law enforcers are bound to look for mistakes among the blacks than they would do with the whites. Discrimination is even evident in the law paying job application fields in which a white man, who has got a criminal record, has got higher chances of getting employed than a black man who has got a clean criminal record. In such a case, the employer is not interested in the records of the employees, but rather concerned with the race of the applicant. Therefore, despite many efforts that are put in the society to show that there is equality in different spheres, intercultural communication still plays as a major hindrance in the achievement of this.

Leadership and Management in Health Visiting Essay

Leadership and Management in Health Visiting - Essay Example "Leader is a person who leads, commands, or precedes a group, organization or a country". "Manager is a person who manages an organization or a group of staff. A person who controls the professional activities of a performer or a player is also called a Manager or a person in charge of activities, tactics, and training of a team." Oxford Dictionary Leadership is a process by which a person influences others to accomplish an objective and directs the organization in such a way that makes it more cohesive and coherent. They carry out this process by applying their leadership attributes such as beliefs, values, ethics, character, knowledge, and skills. Although the position of manager gives one authority to carry out certain tasks, and objectives in the organization, this power does not make one leader, but it simply makes you 'Boss'. Leadership differs in that it makes followers wish to achieve high goals, rather than simply bossing people around. Basis of good leadership is honorable character, selfless service to your organization. In your employee's eyes, your leadership is everything you do that effects organization's objectives and wellbeing. Respected Leaders concentrate on what they are (such as beliefs and characters) what they know (such as job, tasks and human nature) and what they do (such as implementing, motivating, and providing direction). Health Visitors are community health professionals (midwives, comm... Health Visiting is thus at the heart of services for children. Their work is highly valued across the system, and with their public health nursing and family support skills, they are an integral part of children's services. Principles of health visiting are the search for health needs; create an awareness of health needs, influence on the policies affecting health, and facilitation of health enhancing activities. Universality of health visiting service is vital for the early identification of problems. In partnership with health visitors families will continue to receive a health needs assessment. For families with no identified needs, a minimum program is proposed. This will allow Health.Visitor. to target their service to most vulnerable families. Health visiting team can be made fit to respond to the changing needs of health and service care agenda, by building skill mix team with greater responsibilities and accountability. . Sure Start is the cornerstone of government's drive to tackle child poverty and social exclusion. Sure Start works to provide childcare, early education, health and family support services for children below 5 years. These integrated services are delivered through children's centres,which are concentrated in most disadvantaged areas till date.By this year (2006) they are planning to come to the mainstream since local audit has shown that 30% of the country's (U.K.)vulnerable children are living outside this area. This guidance is given in 3 parts to Local authorities, Primary care trusts, Children's Centre Managers and Practitioners. - Section 02 deals with planning and running a centre, Section 03-10 focus on the delivery of services, Section 11-14 focus on the working with different groups. In brief practice guidance states

Reason and Democracy Essay Example | Topics and Well Written Essays - 1000 words

Reason and Democracy - Essay Example To understand how democracy and reason are tightly coupled, it is good to understand the history of human government, and how the various struggles for democracy have been lodged. Looking at the history of democracy, it is good to understand what used to be the alternative forms of government before democracy became the main form of government around the world. History shows as that soon as civilisation of man come around, forms of government that were formed were anything else other than a government. Societies were so entrenched in these systems that those who were on the oppressed side of these other forms of government could almost not be able to comprehend that they could have a free democratic space. Pioneers of democracy such as Thomas Jefferson (Jefferson 5) and his team in America had to use reason in order to determine why a new form of government was not only important but also eminent. In his declaration of independence, for instance, Thomas Jefferson used a language that appealed to reason. In the case of Jefferson, it can be very clear that it is only by being able to appeal to reason that one is able to explain the need and show that democracy is not only imminent but it is also eminent. Reason can be seen as the mother and father of democracy in at least two ways. First, without reason, those who first came up with the idea of democracy, and that there should be a new form of government could not have been able to come up with these ideas in the first place. Looking at history and analysing the various heroes of democracy indicates these people have to reason and realise that the current forms of government at their times were not the best ones. The other reason why reason can be seen as the mother of democracy is the fact that after giving birth to the idea of democracy, reason acts as the nurse that makes sure that this idea is grown and delivered into maturity. After conceiving the idea of democracy, one must use reason to convince at least t wo groups of people about the idea of democracy. The first group is the group that is in the disadvantaged side of the non-democratic system because this group must be convinced that a new form of government can and must be achieved. The fight for democratic governance is not an easy one, and it is necessary to appeal to the reasoning of these people in order to motivate them to fight the hard fight for the new form of democracy. Jefferson and his team seemed to have understood this very well, and they wrote a well crafted declaration of independence that would convince people that they deserved a good governance system and that they should fight it to the bitter end. This technique has since been used by a number of American leaders. The most recent use of this can be seen in president Obama’s (2009) speech in Cairo where he tried to use persuasive language to create rapport between the united stated of American and Egypt and the Islamic world at large. The second group that needs a very clearly stated appeal to reason is those on the softer side of a non-democratic government system. These individuals must be convinced that democracy, in the long run is inevitable and that the sooner they give up and allow democracy to reign, the better. In this case, reason is used to persuade these people that they can do it the hard way or the easy way, but either way, they will have to be let go and let democracy rule. More than anything

Selection methods in recruitment Essay Example | Topics and Well Written Essays - 2500 words

Selection methods in recruitment - Essay Example This essay discusses that the selection of personnel and assessment activities are some of the integral parts of organizational existence. The economic climate and global business environment have witnessed a dynamic increase in the rates of staff turnovers and the consequent reorganization of organizational structures along with the eradication of the traditional concept of ‘job for life’. Consequently there has been an increase in pressure to fill up the vacant positions in the organization with the most appropriately skilled personnel. Additionally the quality of human resources recruited in organizations and their fitness with the structures and processes in the organization also account for the competitive strength of these organizations. The decisions about selecting a candidate and classifying applicants according to the predictions about their work behaviours in future are becoming increasingly critical. There are ample methods and procedures before a company for selecting candidates or making promotion decisions about their employees. Different kinds of assessment techniques are also at their disposal. However, these techniques are commonly seen to fail in the long run. It is seen that there is either a mismatch of skills, or work behaviours different from that expected or even an increase in the staff turnover, depicting a failure of the selection or assessments methods employed for recruiting them. Extensive research has been conducted to trace the reasons for such failures and the ways to eliminate them. However, it is seen that despite the low accuracy of such selection techniques in predicting job performance firms continue to employ them and they remain widely used in today’s organizational scenario. The present assignment seeks to bring forth the reasons why they continue to be popular modes of selection in organizations despite their high failures. It also presents an evaluation of the other selection methods used in organiz ations. Selection Methods in Recruitment The common modes of section in organizations are interviews, bio data, structured interviews, psychological tests, assessments centres etc. Along with skill testing to analyse the fitness of a personal in a particular job, personality tests are also conducted for evaluating heir behavioural fit into the culture of the organization. With the advent of technology and the wide use of the internet, organizations have been increasing undertaking online tests for evaluation of candidates. Interviews are the most common practice of validating tools and skills of candidates to examine how relevant they are and how well they can predict the subsequent performance of the candidate in the organization. Even though the job relatedness of the conventional selection techniques does not follow any particular pattern and are considered to be low they are widely used in organizations despite the fact they are considerably unreliable, subjective and invalid. W hile the necessity of interviews in some form or the other is accepted in organizations, there emerge questions over its validity and reliability when a firm relies on it completely. One explanation which had been forwarded by researchers is that different interviewers assess candidates different and such irrelevant aspects such as race, sex, appearance, age are given prominence which introduces biasness in the way interviewer evaluate the candidate. Structured interviews conventionally include questions which are developed though a form of job analysis which consequently limits the subjectivity of the assessment. Conducted through standardised procedures structured interviews brings a direct link between the content of the interview and success of the job. However, despite having a high degree of validity and relatedness structured interv

Multicultural Education Essay Example | Topics and Well Written Essays - 500 words - 1

Multicultural Education - Essay Example The race is an insightful contributor towards the increasing need to embrace multicultural education around the world. In regard to the increasing interaction of different communities online and physically particularly on an education platform, multiculturalism is promoted by the author in lengths and depths. By offering a global approach from the United States and European perspective on the topic, the author is clearly relevant to the contemporary socio-economic and political dynamism among learners. In an effort to achieve cultural diversity among the various people of diverse backgrounds in schools, the author emphasizes the importance of tolerance for a better learning environment. Despite demonstrating the outstanding significance of this concept, the text has some information gap in regard to comparative statistics to support facts. The author introduces the role of multicultural education. In the United States, the author portrays a society of multi cultural characteristics with significantly diverse socio-economic and political viewpoint. In that respect, Learners must be accommodated in their different cultural backgrounds to promote expression of individual’s views with the goal of achieving convergent interests. The author emphasizes education system as critical in imparting democratic spirit in the society as it involves learners from childhood towards adulthood. The text is relevant to the increasing need to expand democratic approach in conflict resolution and sound governance systems in this era of globalization.

Principles of fundraising and sponsorship Speech or Presentation

Principles of fundraising and sponsorship - Speech or Presentation Example The donations have culminated into the establishment of new initiatives and services aimed at making the club survive. The Saints under 14s have benefited from the Paramed aimed at new strips as they will be kitted out in a brand strips. Basically there is black and white kits that are distinct are from Paramed UK. The deal helped the club to survive based on its financial significance as the club was faced with financial constraints. Despite the pros attached to such arrangements, serious strings are attached to sponsorships, and fundraising felt through several risks. Requesting for such fund requires in-depth understanding of principles of sponsorship and fundraising as well as the techniques used to obtain the donations. Donors need to be convinced by showing higher levels of accountability and transparency within the public sectors. Evaluation of fundraising, donations and sponsorship proactively is key in promoting ethical standards as it ensures that grants obtained serve the public interest. Despite the fact that donors expect nothing in return, they donate in order to change lives of other people and hence need for transparent and accountability. The sponsorship framework and Fundraising or Donation arrangement should not restrict Services ability to execute its roles impartially and to completion. The contract should outline that the Services functions shall proceed to execute its business impartially and fully without interference from the arrangement proposed (Norton 2007, p. 111). For instance, daily activities of ambulance van should not be shuttered by fundraising activities but to ensure its continuous operational tasks. The contract has a separate statement providing for termination of sponsorship if the arrangement compromises Services functions. For tender-attached sponsorship, the contract should ensure non-favoritism for parties involved. Secondly, there should be non-existence of real and apparent conflict between

A Publicly Owned Large Company Research Paper Example | Topics and Well Written Essays - 1000 words

A Publicly Owned Large Company - Research Paper Example This case briefly analyzes the real world problems which a company might face while having a meeting in order to select its supplier. If the problems are not resolved at the first stage i.e. while having meetings, then there are considerable chances of facing immense amount of problems later on. This case provides insights about the potential problems which may arise at the stage of having first meeting with the potential supplier. Central Problem   Jill Turner, representative of Success Inc. is having a meeting with Supplier A Inc. in order to find out if they are competent enough to be selected as a supplier for Success Inc. During the meeting, Jill encountered various issues. These issues included the strange quietness of the representatives of Supplier A Inc., not checking the business cards of the representatives which can be considered as Jill’s own mistake, not being sure where the headquarter of the company is located and not knowing who is the right person to talk w ith. In the subsequent paragraphs, discussion has been provided about how to cope up with such problems, why these problems arise and what were the reasons behind such problems. Statement of Objectives   There are certain areas which need to be analyzed and evaluated before commencing a meeting. If that is not done, than it might lead to wrong decision making and ultimately will end up in against of the company. Wrong decision will definitely cause loss of money and time to the company therefore it is required to be very careful before taking such big decision. This case analyzes what mistakes can occur during meeting while selecting a supplier. Areas of Consideration (SWOT)   Strengths The strength of Success Inc is that it has smart representative namely Jill Turner, who sincerely looks for all the pros and cons before choosing any supplier. Success Inc is very cautious while selecting a supplier which is the strength of this company. Success Inc.’s representatives hold meetings with each of the potential supplier before selecting the right one. They analyze and evaluate each and every aspect so as to avoid any serious problems in future. Weakness The weakness which Success Inc. possesses is that its representatives at times make such mistakes which can cause loss of time and money to the company. Representatives of Success Inc need to be more careful and must not be so judgemental. Threats By not analyzing own mistakes and ignoring those mistakes, there are chances for the supplier to get the deal by showing misleading facts and figures. Success Inc. needs to analyze each and every single point before coming to the final decision otherwise the suppliers might take the advantage and therefore the threat of bargaining power of supplier can increase substantially. Opportunities After analyzing the case, it seems that the opportunity that Success Inc. has is that they usually do not have time pressure. By not being bounded to the time frame, they can take as much time as they want and can study comprehensively about each supplier. The financial position, previous performance, lead time, delivery and quality are some areas which need to be considered thoroughly before taking any final decision. Time Context Success Inc. doesn’t have any time pressure which means that they are not compelled to launch a particular product in particular time frame which gives Success Inc. an edge in studying more carefully about the potential suppliers. Alternative Courses of Action   Selecting an appropriate supplier is not an easy task for large companies. There are many areas to consider before selecting a supplier. Most often, companies mislead the information so accurately in order to get the deal that it becomes difficult in considering if the facts

Information Systems Essay Example | Topics and Well Written Essays - 2000 words

Information Systems - Essay Example The next to be exhaustively discussed are the differences that make a company unique. A detailed examination of these unique qualities will be essential in determining how ERP or any software implementation no matter how the company complies with the standard as mandated by the software still manages to operate differently. Using SAP as an example of how applications affect or impact companies within the same industry this paper shall detail the way SAP is implemented. The details of how SAP is implemented hopefully would provide a logical explanation on how the company’s collective consciousness and culture influences the decision of every individual in the company. This paper shall similarly examine how the collective consciousness and culture is displayed if not manifested. ASAP or accelerated SAP is the process in which SAP is implemented or rolled-out in every company. The utility of the ASAP itself indicate the commonality of how SAP is implemented indicating that each c ompany has the same processes that could be automated by SAP (Khan, 2002). However, even if SAP’s implementation is managed uniformly, there exist variances in the way companies operate even if they are using the same application or were implemented in the same way. According to ASAP, the business processes of each company intending to implement SAP could be documented uniformly using the same discovery techniques. However, ASAP equally mandate that in the documentation of the business processes it is imperative that the business process owners (BPO) and the subject matter experts (SMEs) assist if not be the one to define the â€Å"as is† processes. In the development of the â€Å"to be† process, the SMEs and the BPOs are not only needed but is also essential (Keller & Krugger, 2002). The standards The IFRS (International Financial Reporting Standards) are not only accepted by companies all over the world but governments likewise use the standards imposed by IFR S in conducting audits to companies. The provisions and interpretations of each terminology are therefore the uniform and constant all over the world. The format in which reports are printed or displayed on screen is equally identical (Mackenzie, Coetsee, Njikizana, & Chamboko, 2011). To illustrate: The way â€Å"revenue† is defined in one country or specifically in a company is the same all over the world. This is similarly true for the word â€Å"expense† and â€Å"taxable income† and a few more. The way debit and credit is qualified is also the same including how it is presented in the books or ledgers of the company (Bragg, 2010). Regulatory Reports are the reports mandated by the government. A close examination of the reports of each country would reveal that even though the format maybe different but the contents are generally the same. The way Financial Statements are presented all over the world is also the same. This would include the way books are main tained and logged (Morley, 2009). Standard Management Reports for each industry is also the same. The contents are the same even the presentation is the same. However, even SAP acknowledges that there are some management reports containing specific information that are needed by a certain

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

Write choose - Term Paper Example In this respect, the question of how man started hunting and the methods that he applied comes into the fore. Thus, this discussion seeks to assess the methods applied by the early man during hunting. Hunting by fire is one of the methods that have been discovered being used by the early man. Fire was among the first discoveries that early man made, which changed the lifestyle of early man drastically, especially as related to the eating habits of man (Nitecki, 5). The earliest archeological evidences have indicated that the early forms of man were eating raw foods, but the discovery of fire came in handy as a means of enabling man eat a variety of food, as well as helping man insulate against cold. The sooner fire was discovered to be an important item that could change the life of man in different ways, the sooner it was also adapted as a hunting tool, where man could chase after the animals with a lit torch of fire towards the cliffs (Stanford and Bunn, 4). This way, the animals could get injured as they fell down the cliff and man would be able to take them and use them for food. Another method that has been discovered as having been used by early man in hunting is the use of crude weapons such as stones (Nitecki, 12). Amongst the important tools that have proven useful for man during the early human forms is the stones, which were not only used as weapons for protection and security against harmful animals, but also as a tool for digging tubers and roots that man used as food during those days. Eventually, man adapted the stones as tools for hunting, which they could use to chase after animals and throw at them, thus injuring and incapacitating the animals (Stanford and Bunn, 9). The same tools would be used to kill and then slaughter the animals, owing to the fact that the early form of humans had not discovered metallic or any other form of

Tuesdays with Morrie Paper Essay Example for Free

Tuesdays with Morrie Paper Essay Tuesdays with Morrie is a classic piece of literature that depicts an atypical student-teacher relationship. An unusual twist of fate takes the student and this book’s author, Mitch Albom, to once again cross the path of his college professor, whose terminal illness brings both of them to compose their final thesis.   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   Morrie Schwartz started out as Mitch’s sociology professor back in Brandeis University, Massachusetts.   Mitch could be described as the typical college student who hid beneath his tough impression in order to compensate for his being a year younger to be a freshman. Mitch was a good student and in the long run, despite his initial impression of Morrie, took to the professor’s classes and belief that educating was experience over theory. With their classroom and one-on-one discussions coupled with the number of sociology classes that Mitch took under Morrie, the professor finally encouraged Mitch to write an honors thesis, a year-long task which Mitch proudly submitted to is teacher by spring of that year.   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   Sixteen years after, life has drastically changed for both of them. Mitch became the career-chasing sports journalist, a job he had traded for his dream to become a piano player. Morrie, on the other hand, had been diagnosed with amyotrophic lateral sclerosis (ALS), a brutal illness of the neurological system. It was a typical night in the life of Mitch, as he was changing channels when he heard the once familiar Morrie Schwartz named in one of the popular nighttime shows on television. It featured his old professor, now stricken with the illness, and all their memories back in college came rolling back to him, including the promise he made during graduation that he would keep in touch with his once favored teacher, one that he never fulfilled.   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   Back on campus, the relationship of Morrie and Mitch’s as professor and student proved promising. One was a very dedicated teacher, the other, a willing student. Their initial acquaintance was concluded with Morrie hoping that one day, Mitch, as many of his friends called him, would also be his friend.   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   With most of our generation being in school at one time or another, it would be a truthful observation to say that the relationship between Morrie and Mitch is not the typical teacher-student relationship that we know of. In this time and day, students come and go, and seldom do teachers have the steadfast dedication that Morrie maintained to leave a lasting impression on his students. Although their relationship started out in academics, it eventually developed into a friendship where the old professor became a mentor of life to the young student. They sometimes sat together to eat, had lively discussions about human relationships, and through all these Mitch had agreed to become the player of Morrie, whom he started to call â€Å"Coach.† Despite the need to make up for lost time, the time they met once again, and the Tuesdays after that defined a relationship that was unquestionably one that naturally became a continuation of the friendship they once had.   That reunion after 16 years marked a renewed beginning of a deeper relationship between the two. Both had agreed to meet on Tuesdays immediately after making the pact that the remaining days of Morrie would be devoted to the composition of the â€Å"literature of death.† This would discuss what Mitch pertained to as the issues of his generation such as death, fear, aging, greed, marriage, family, society, forgiveness and a meaningful life.   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   The tape recorded topics of the â€Å"Tuesday people† started with a discussion about the world. Morrie described it as a world where dreams were traded for bigger paychecks, something which Mitch was very guilty of. The culture that the world has generally does not make people feel good about themselves. Morrie suggests that if this is what culture sells you, then you don’t have to buy it. But because of the daily exposure of people to these ads and their promises of beauty, fame, or fortune, they are lured to thinking that being themselves is not enough. As such, each day they fall prey to this very culture that promulgates that what is trendy is equivalent to â€Å"normal.† In the long run, people walk around leading meaningless lives, busy doing things they believe to be important. In their desperation to put meaning in their lives, they chase the wrong things. After chasing these wrong things and end up finding out that they too, are empty, they keep running. And unfortunately this goes on until the day they leave this world.   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   Each morning that Morrie wakes up and feels sorry for himself, he cries for a few minutes and then moves on, deciding that wallowing in self-pity would not be the way he wanted to live his remaining days. This is what he calls detachment, learning to let go after feeling the moment. Dying is about accepting it as a natural phenomenon in this world. Humans should not be thinking that they are above nature but rather, a part of it. As one of Morrie’s favorite stories said, the wave is not going to crash into the shore and die. Instead, it had to remind itself that it was part of the ocean.   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   When asked about the regrets he had in life, Morrie simply said that it is about vanity and pride. He regretted losing a friendship because of pride. This is where the topic on forgiveness comes in learning to forgive yourself, and then forgiving others before you die. Most important of all, despite his impending death, Morrie faced it with the acceptance of a child. Instead of letting the terminal illness disintegrate his spirit, he enjoyed his dependency on other people as a baby would on a nurturing mother. Ironically, awaiting his death ultimately served as their biggest lesson about living. As Morrie put it, â€Å"once you learn how to die, you learn how to live.†   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   Topics in their Tuesday sessions dwelled on the importance of love, spirituality, responsibility and awareness. Morrie pointed out that the most important thing in life is learning how to give out love and letting it come in. Quoting his favorite poet, Auden, Morrie frequently told Mitch, love each other or perish. Over and over throughout the book, Morrie emphasized the importance of love and that it would be the only way for your memory to be alive when you’re gone. If the people you leave will remember that feeling, even if you die, you will never really go away. Although death puts an end to life, it doesn’t end a relationship. The only reason people wished to stay young, as the professor said, was because they never had satisfied and fulfilled lives. It is only when one was able to find meaning in life that they were able to move forward and look forward to their destiny.   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   What Morrie wanted Mitch to learn was to live a life that was devoted to loving others, the community around you, and being able to create something that gave you meaning and purpose. After loving others, one needs to be able to love the community they live in. Even if every society has its own problems, Morrie proposes that the answer is not about running away but about creating your own culture and embracing your community like your own family. Morrie taught about investing in the human family, in people, by building a community of those you love and those who love you. Showing off to people above you is futile because they will always be looking down on you while showing off to those in the bottom will only cause them to envy you. Status, according to Morrie, gets you nowhere. As the professor once exclaimed, there was nothing wrong with being number two. Who cares?   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   Other important values during the final days of Morrie were about being compassionate and taking responsibility for each other. He rationalized that the world would be a better place if people had learned these basic lessons in life: regrets, acceptance of death as part of nature, the importance of family, showing emotions, love, and forgiveness. In fact, when Mitch asked Morrie how he wanted to spend his â€Å"last day† on earth, it was neither about being able to experience the exotic nor being a VIP. Surprisingly, it was just about getting in touch with nature, with the people he loved, and enjoying the simple things that truly mattered in life.   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   Among all the things that Mitch has learned from Morrie during his final days, it is the importance of love that proved very essential for me. Even if one had all the riches in the world, clichà © as it may sound, material satisfaction is never enough. Morrie in his final days, as he was stripped of his independence, had learned to be more alive in giving himself, his ideas, to those who wished to hear him out—family, meditation teachers, discussion groups, old students, and friends. He had found more meaning in being able to listen to the problems of other people and contributing in whatever way he can to its solution. He had achieved what he had aspired for in life by having his loved ones surround him in death, rather than hearing of praises when he was on the grave. Morrie imparted the basic idea that indeed, death was not the end of a relationship.   Death was just a phenomenon of nature that we had to understand, that life was not about what society dictated. Life was about living in the moment, being happy with the simple things in life. Not running after the next job, or the next big thing. Paycheck was never in Morrie’s equation of living a happy life. A meaningful life was more about being in touch with those you love, and manifesting that love through affection and uninhibited communication.   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   As life comes to an end, you only cared about the legacy you leave in this world. How far has your influence gone? Have you told people you cared about that you loved them? Do you want to leave with regrets? Seemingly mediocre to many, these are questions that Morrie challenges us with. As we are posed with these questions, Morrie leaves us the inspiration that we ought to deal with life as if we were dancing with it. Dance with all your heart, with all your might, as if nobody’s looking. If Morrie Schwartz only had the chance, he would have danced his life away, until his last step, until his final breath.

Future professional of tourism

Future professional of tourism Introduction New tourism is an important subject for future professional of tourism. To work in this sector we have to be aware of new form, new tendency and new destinations. Travel sellers have to know supply and demand in this field. Our file is a glimpse of some new ways of travel and new destinations. We need to keep watching on this new form of tourism because it is very competitive sector. Thats why we have chosen to describe two new destinations and two new form of tourism. In one part we explain couchsurfing that is a new form of tourism based on people exchanges. It is almost a way of life with values and aspirations. Une phrase sur la partie de reb. In a second part, we show two new destinations. First Bulgaria, its number of visitors has increased by 4000000 in 8 years. This country with a coast on Black sea is more and more visited especially by Europeans. Phrase sur partie de Reb. Tourism evolves and new forms are created Couch surfing CouchSurfings definition Couchsurfing is a new way of travelling based on sharing. An organization based on Internet (www.couchsurfing.com) manages the connections between people. CouchSurfing is an international non-profit network that connects travelers with locals in over 230 countries and territories around the world. A couch or a bedroom is offered to a visitor by a local for his stay. Since 2004, members have been using this system to come together for cultural exchange, friendship, and learning experiences. Today, over a million people who might otherwise never meet are able to share hospitality and cultural understanding. Our mission as an organization is to create inspiring experiences: cross-cultural encounters that are fun, engaging, and illuminating. These experiences take many forms. CouchSurfings initial focus was on hosting and surfing (staying with a local as a guest in their home). Alongside these core experiences, we now also facilitate a growing array of activities and events.[1] CouchSurfing members share hospitality with one another. These exchanges are a uniquely rich form of cultural interaction. Hosts have the opportunity to meet people from all over the world without leaving home. Surfers, or travelers, are able to participate in the local life of the places they visit. The CouchSurfing community continues to expand its horizons. Members are always finding more ways to connect and learn about each other. Every day, people across the world share coffee, camping trips, meetings, language exchanges, discussions and all sorts of other experiences. Who and how runs CouchSurfing? Casey Fenton launched the site on Jan 1, 2003 with co-founders : Dan Hoffer, Sebastien LeTuan, and Leonardo Bassani de Silveira. Casey continues to help CouchSurfing as Executive Director of the organization. The CouchSurfing organization has no physical location. Instead, it exists in the collaborations of diverse people from around the world. The strategic direction of the Couchsurfing organization is composed by a Board of Director and a Strategy Team. Each member of these two groups brings different specialized skills. Members of strategy team: Casey Fenton, co-founder and Executive Director; Mattthew Brauer, General Manager; Jim Stone, Chief Operations Officer; Weston Hankins, Chief Technological Officer; Cameron Mills, Project Portfolio Manager. There also some full-time employees and contractors. They have a variety of roles from building and maintaining the website to organizing finances. Finally, some part time volunteers help them to manage the organization. They are Couchsurfing members and they greet new members, report website bugs and answer member questions. CouchSurfing is a non-profit organization, funded entirely by the donations of members. According to the web site, every month, thousands of CouchSurfers choose to support the community by getting verified, an identity check that includes a donation. Other members choose to make independent or additional donations. Contributions help to pay for the costs of running the website, like server hosting, storage, database maintenance, mapping software, and many other costs[2]. Each positive experience between members costs 24 ¢ USD in CouchSurfing operating costs. The goal of CouchSurfing has never been about money, and using the site is free to all members. CouchSurfings non-profit status legally means that all resources must be spent directly on achieving the mission rather than creating profit for private interests. Few statistics 1775916 Couchserfers are travelling sharing homes in the worlds. There are 236 countries represented and 70637 cities for 318 languages spoken. The 10 countries most visited are United States with 395657 visitors that represent 22,3 % of couchsurfers, Germany with 168807 visitors (9,5 %), France with 150939 visitors (8,5%), United Kingdom 85587 visitors (4,8%), Canada 85544 visitors (4,8%), Australia 50821 visitors (2,9 %), Italy 50652 visitors (2,9%), Spain 48858 visitors (2,8%), Brazil 48503 visitors (2,7%) and Netherland 35661 visitors (2 %). We note that almost all continent are represented in the top-ten, except Asia but China just come in 12th position. Regarding the most visited cities Paris is on first position, then London and Berlin comes on third position. The average age of surfers is 28 and 85 % of surfers have between 18 and 35. Our opinion Couchsurfing is a meaningful new way of travelling. It creates connections between cultures and can enrich lives of everybody. It is more than a way of travelling it is a way of living with many values like exchange without profit. We think that couchsurfing is a door to experience new point of view and new culture by travelling or welcoming. It is also a tool to travel more especially for young people. Indeed, even if it could be less comfortable than hotel room, it is free. Travels help to built mind and this way of travelling permit to travel more, further and better. Partie de Reb New destination appears Bulgaria Bulgaria is a small country in south-eastern Europe. It have frontiers with Romania, Serbia, Macedonia, Greece and Turkey. This country owns coasts on Black sea. The climate and the relief permit to develop a large number of touristic products. In 2000 the number of visitors were 2100000, it increase and there were 6000000 tourists in 2008. Bulgarias assets The natural landscape is one of the most important assets. First, mountains and high peak are attractive for ski tourism. Most of the 44 ski resorts are located in western country around Sofia, the capital city. The most famous are: Aleko ski center on Vitosha mountain at 22 km of Sofias city center with 29km of ski runs, Borovets ski resort on Rila mountains that is a high class resort with luxury hotels, Bansko in Pirin mountain, thats one of the new ski resort in Bulgaria with 56 km of ski runs and a great off piste skiing, Pamporovo ski resort in the heart of Rodopa Mountain is the southernmost resort in Europe. Then, we can find the Black Sea Coast famous for its fine sanded beaches, and perfect temperatures of water and air. The northern and the southern coast are different. On the north tourists can find clean and calm sea surrounded beaches with fine grain golden sands. The most famous and the most frequented sea side resort are Golden Sand, Albena, Roussalka, Riviera, Slanchev Den (Sunny Day), St.Konstantin and Elena. On the south, picturesque bays and steep rocks coexist with spacious beaches and sand dune. The coast provides wonderful nature and modern constructions on holiday villages like Elenite, Sunny beach, Nessebur, Sopozol Rural tourism is another form present in Bulgaria but less significant. An unconventional form of tourism Health tourism is a great part of tourism in Bulgaria. With over 600 mineral springs with temperature between 10 °C and 120 °C, Bulgaria is a thermal destination. Pavel Banya, Hisar, Velingrad, Narechen, Vurshets, Kyustendil and Momin Prohod, near Kostenets are the most famous of the health resort. They treat different diseases like bronchial asthma, disturbances of locomotors system, cardiovascular diseases, neurological disorders Another Health or medical tourism exists in many forms. People travel in Bulgaria for medical, dental or surgery care, especially from United States and developed country where medical treatment are more and more expensive. Health Tourism is a combination of wellness and healthcare coupled with leisure and relaxation. Diet Center: Some tourists travel to lose weight and the most famous clinic is located in the sea side resort of St-Konstantin and Elena. A stay in the clinic last between 10 and 20 days and cost between 500 and 2000 Euros including catering in hotel, a medical consultation, medical exams and a diet program for each patient. Plastic surgery: It attracts tourists because of the low price and the quality of services. In the middle of 90s a lot of clinics have opened and a high competition appear. The clinics directors had to invest in high technology and high qualified staff. As example a breast augmentation cost on average 6000 Euros in France, England or Germany and only 2500 Euros in Bulgaria. Tooth care: The prices are cheaper than in Western Europe because they are align on Bulgarian standard of living. We can find a lot of good clinics in big cities like Sofia, Burgas, Varna and Plovdiv. Some tour operator offer medical trip to their customers, they organize the whole stay. Global medical travel in USA and BGmedical travel in Bulgaria are specialized on medical travel. Our opinion According to us, it could be interesting to travel abroad for surgery or medical care. Indeed, in many occidental countries a lot of people are underinsured or uninsured. It means that many people have to pay for their medical care. According to a Harvard study, in USA half of personal bankruptcies are related to medical expenses. We think that its sometimes the only solution to cure decay. People have to be careful. First of all, they must check the procedure and compare with their expectations, inquire about follow-up care needed, time required for recovery, physical therapy etc Then, they have to select the hospital by considering its accreditation, awards and recognitions, facility and equipments and statistics like success rates. Finally, its essential to heck the certifications, training and repute of the surgeon. www.couchsurfing.com Attached document n °1: Couchsurfing International,Inc. Income and Expense statement 2008 These statistics are generated on March, 31th 2010 at 5:37 am.

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