Education Opens Doors

â€Å"Education opens doors†. Do you agree? I strongly agree that education opens doors. Education provides us with the opportunity to learn new skills and to meet new people in order to share ideas and discover and develop new concepts. For people, it opens up a world of opportunities, reduces the burden of disease and poverty, and gives greater voice in society. For nations, it opens doors to economic and social prosperity, spurred by a dynamic workforce and well –informed citizenry able to compete and cooperate in the global arena.Education can be the difference between a life of grinding poverty and the potential for a full and secure one; between a child dying from preventable disease, and families raised in healthy environments; between orphans growing up in isolation, and the community having the means to protect them; between countries ripped apart by poverty and conflict, and access to secure and sustainable development. The education and skills we acquire affe ct all aspects of our lives.They have a decisive influence on our ability to find and keep a job, our capacity to take part in society, our social status and self-esteem, our family relationships and our ability to help our children through school. Better educated and more skilled people are more likely to be in work, earn more and contribute more productively to the local economy and community. Knowledge and skills provide individuals with their surest route into work and prosperity, helping to eradicate the causes of poverty and division in society.Education must also recognise that for particular minority groups other factors including discrimination, contribute to underachievement and compound its effects. Today, the value of education, in general, is highly underestimated. Education has minor as well as major purposes. However, the importance of education is quite clear. Education is the knowledge of putting one’s potentials to maximum use. A human being is not in the pr oper sense until he is educated. The importance of education is basically for two reasons. The first is that the training of a human mind is not complete without education.Education makes man ideas have background and supporting facts to whatever theories he has. We are capable of making sound decisions when we have resourceful information. When you are exposed to different ways of thinking and other perspectives, you are more likely to make a decision based on some forethought. And the second is that only through the attainment of education, are we enabled to receive information from the external world; to acquaint us with past history and receive all necessary information regarding the present.Without education, it is as though we are in a closed room with just one window to look out of and one door. Education is a great tool for our self enhancement. It gives us a sneak peek at the cultures and values of the world. Subjects like history, politics, religion and humanities can make s us much more accommodating, sympathetic to other cultures, race and religion resulting in a better bond among international communities.By learning about others values make us able to perform at our best latter in our life contributing to sound political, business related or economic decisions; it also gives us the readiness to work internationally or even locally in a diverse work force. Math and science classes give us the more than just a few basic skills to run the accounting of our life. Math and its deeper studies can help us to becoming good engineers, architects or accountants. Science and its deeper studies can lead us to contribute to the advancement of technology in the new millennium.In conclusion, education fills up the empty ignorant minds to bring about positive changes, which affect individuals, society, nations and then the world as a whole. Until we learn we don't know the benefit of learning; until we achieve knowledge we don't realize how ignorant we were. The world without education would be a world full of disorder. Therefore, to be successful in this life we must carry on the pursuit of enhancing our skills and knowledge through the virtue of education. That is why I want to study medicine in order for me to have a better future and more opened doors.

Nike Innovation

Nike Inc. Prepared by: Chuck Viasi MBA 330 – Innovation and Technology Management August 11, 2012 ————————————————- Executive Summary Nike, Inc. is a globally-recognized athletic sports apparel company with strong brand loyalty. The foundations of Nike’s success today were established by its Co-Founders Phil Knight and Bill Bowerman in 1972. As an athlete and a coach, their relentless pursuit of improved athletic performance instilled a competitive spirit in the culture of Nike. As such, the organization’s culture is one of the key reasons that Nike excels in this industry.We will see how the management style fosters innovation, and how the competitive spirit blended with curiosity and a constant scan of the external environment feeds the creative process. The company has become adept at integrating their knowledge into innovative approaches to improve athletic performance and connect with their customers through design and marketing. Our research on historical trends and processes within Nike indicates that the company’s core competencies are innovation and marketing; the underlying reasons the company is now the most recognized and coveted sports brand in the world.As Nike faces increased costs for materials, the company has made a strategic shift to couple sustainability principles with innovation to create a better company that can, in turn, can make a better world for all of us. Ultimately, this strengthens the company’s ability to compete globally in the future as well as positively impact society. Executive Summary (Stoney/Jen)1 Table of Contents (Stoney/Jen)2 Nike’s Mission Statement (Jen)4 I. The Business of Nike (Jen)4 A. Historical Innovations (Isaac)4 B. Portfolio of Products (Isaac)5 II. Product Life Cycle (Isaac)5 III. Business Model (Isaac)6 IV. SWOT (Stoney)7A. Strengths (Stoney)7 i. Strong Cap italization (Stoney)7 ii. Globally Positioned (Stoney)7 iii. Strong Brand Recognition (Stoney)8 iv. Solid Barriers to Entry (Stoney)9 v. Innovation (Stoney)9 B. Weaknesses (Stoney)9 i. Outsourced Manufacturing (Stoney)9 C. Opportunities (Stoney)9 i. Professional Sports Market (Stoney)9 D. Threats (Stoney10 i. Severe Competition (Stoney/Jen for Adidas)10 ii. Global Economy (Stoney)11 E. How do Nike’s Strengths Reinforce Nike’s Opportunities? (Stoney)11 F. How do Nike’s Weaknesses Relate to Threats? (Stoney)12 V. Nike’s Value Chain (Stoney)12 A. Make (Stoney)12 B. Move (Stoney)12C. Sell (Stoney)12 D. Use (Stoney)13 E. Reuse (Stoney)13 F. Plan (Stoney)13 G. Design (Stoney)14 VI. Porter’s 5 Competitive Forces (Stoney)15 VII. Organization (Jen)16 A. How the Culture Supports Innovation and Success (Jen)16 B. Org. Structure for Optimal Alignment with Customer Markets (Jen)17 C. Breaking into New Sports with Independent Teams (Jen)18 VIII. Innovation Proce ss (Jen)18 A. Innovation Kitchen and Sources of Inspiration (Jen)18 i. Athletes (Jen)19 ii. Customers: Lifestyle Trends (Jen)20 iii. Deep Dives (Jen)21 iv. Art, Artists and Buildings (Jen)21 B. Experts, Incubation and Collaborations (Jen)22IX. From Idea to Commercial Product (Jen)22 X. Product Introduction to the Market (Jen)24 A. Marketing Strategy (Jen)24 B. Event Pacing and Limited Edition Products (Jen)25 XI. Integrated Strategy: Sustainability and Innovation (Jen)26 A. Nike and China (Isaac)26 B. GreenXchange, Considered Design, Considered Design Index (Jen)27 C. Impact on Corporate Goals and Strategy (Jen)28 XII. Conclusion (Stoney/Jen)28 References29 Nike’s Mission Statement: To bring inspiration and innovation to every athlete* in the world. *†If you have a body, you are an athlete. † ————————————————- I.The Business of the Company Nike (NYSE: NK E) makes high performance athletic clothing, footwear, sportswear, and equipment. The company is headquartered in Beaverton, OR, and employs more than 30,000 people. Nike is the most recognized and coveted sports brand in the world, valued at $10. 7 Billion. (Nike, Inc. , n. d. ) As their Mission Statement indicates, Nike innovates for all athletes – from elite to everyday athletes – to improve sports performance. Nike markets its products under its own brand, as well as Nike Golf, Nike Pro, Nike+, Air Jordan, Nike Skateboarding, and subsidiaries including Hurley International and Converse.The company also operates retail stores under the Nike town name. A. Historical Innovations * In 1962 Bill Bower man and Phil Night- Launched Blue Ribbon Sports (Tiger Shoes) with 500 dollar mutual fund. * 1978-Blue Ribbon Sports renamed themselves to NIKE. * 1980- Nike IPO and became publically traded. * 1980- First air sole shoe system Nike runner shoe * 1984-Signing of Michael Jor dan and first Air Force one basketball shoe. * 1985Air Jordan Revolution- 30 plus versions of air Jordan’s * 1989-Waffle shoe sole incorporated by adding rubber to a waffle machine. 2000-Nike shocks introduced and Nike portfolio formed * 2003- Nike ID shoe customization- allowing customers to make customized shoes from a computer, * 2006- Nike shocks tech * 2008-Nike Research lab environmentally friendly * 2011, Nike collaborated with Tom-tom for the launch of Nike+ Sport-Watch GPS. * Present Nike Innovation Kitchen- green products and greener product cycle. B. Portfolio of Products Nike’s portfolio consists of Converse, Nike Golf, Nike Baseball, Air Jordan shoes/Accessories, Hurley International.Nike is a leading designer, marketer and distributor of athletic footwear, apparel. Nike has done a spectacular job of diversifying their portfolio and being able to implement competitive advantage in all brands. The Company’s key product lines consist of: * Shoes * App arel * Equipment & accessories ————————————————- II. Product Life Cycle NIKE’s products and services falls in the growth stage of the product life cycle due to their ability to diversify products and rapid growth in sales and profits.According to knowledge. com â€Å"Nike is at a ranking of #135 in revenues generated by America’s 500 largest corporations. Of the nineteen billion fourteen million in revenue 2. 1 billion  was profit. † Nike is the niche when it comes to introducing new product and that is why there are at the growth stage allowing them to produce capital at a rapid pace. They always have new products coming out and new angles of approaches and that keeps them in the growth areas of the product life cycle. ———————————————— - III. Business ModelNIKE has a gift of trying new ideas that other organizations are too scared to attempt. The Nike business model consists of five steps. 1) Conducting research 2) Manufacturing product shoe, clothes, etc. 3) Retail 4) Consumers 5) Down cycling. , Nike introduces products to the market with athletic endorsements and mass marketing. They have the products assembled overseas for a fraction of the cost it would cost to manufacture in the in the United States. The Nike Corporation is known as innovators for making a product at low cost and charging an above average price in retail. I believe that this model works well for Nike as every time they have a new shoe come out that is expensive and overpriced they still have people waiting in line overnight for their shoe product. Nike Business Model ————————————————- IV. SWOT Analysis Strengths| Weaknesses| Well c apitalized| Outsourced manufacturing| Globally positioned| History of human rights scrutiny| Solid brand recognition creating competitive advantage| | Strong barriers to entry| | Innovation/product development| | Environmentally conscious culture| | Marketing| |Opportunities| Threats| Professional sports market segment| Severe competition| Growth in global apparel market| Global economy| Leadership in US market| Third world governments| Global marketing initiatives| Black market/counterfeit market| | | (MarketLine, 2012) A. Strengths i. Strong Capitalization: According to the Nike 10K report net income for 2011 was $2. 1 billion; although this is a drop from the previous year Nike still maintains a strong capital position. Last year Nike also saw their inventory go up as a result of future orders and the company repurchased $1. billion dollars of class B stock which is part of a 4 year $5 billion repurchase program. Thus far Nike has repurchased 30. 4 million shares for $2. 3 billio n. Even with this repurchase program Nike still has $4. 5 billion in cash, cash equivalents or short-term investment reserves so they are well positioned with capital for the future. (Nike, Inc. (2011) ii, Globally Positioned: Nike was ranked #1 in shoe and apparel revenue in 2011 and remains positioned well for the future. In the global shoe market there are two main players, Nike, a US-based company, and Adidas, a German company.Nike remains focused on defending their leadership position in the industry by signing contracts with the NFL, NBA, MLS, European soccer teams, and college sports teams. One of their advertising plans has historically included elite athletes like Michael Jordan, who still has the highest ranked athletic shoe in the history of the industry. Adidas sticks to its core values of â€Å"function first†. They also market their shoes by fashion, as modern, and as cool enough. While Nike is king in America, Adidas is the leader in European markets.The Adidas brand had a market share of 38% while Nike was right behind at 37% (Jones, 2011) In 2006 a study by William Hanrahan positioned global shoe marketers as follows: Hanrahan, (2008, p. 8) This graphic shows all the leading brands of shoes with their global positioning as of July 2006. Nike is located in the average to low affluent market with its main competitor being just a little larger (at that time) and a little higher in affluence. iii. Strong brand recognition creating a competitive advantage: The Nike swoosh is a recognized brand logo throughout the world.While Nike is known to charge a premium price for their average affluent market they are also known for quality and catering to the needs of the athlete. The target market for Nike is the young athletes and they are loyal to Nike as through advertising, Nike connects to this audience by demonstrating a keen understanding of their psyche and lifestyle. iv, Solid barriers to entry: Nike’s strong global brand has created a barrier to entry in the sports market. Other barriers include high capital requirements, high research and development costs, and keen innovation instincts. . Innovation: Innovation is a core competency for Nike as they pour investment dollars into research & development. The â€Å"Innovation Kitchen† generates the majority of their innovative ideas, which will be discussed in another part of this report. B. Weaknesses: i. Outsourced Manufacturing: One weakness is the fact that nearly all of their apparel and shoe manufacturing is outsourced. While this is an advantage from a cost perspective, and allows Nike to focus on their core competency, Nike gives up a lot of control by outsourcing to suppliers.The risk involved includes problems with governments and a workforce that that is out of there control. Another weakness that the company has displayed in the past is human rights and they are constantly under the pressure by human rights groups. C. Opportunities: i. The pr ofessional sports market: Nike’s target market has always been the athlete. The market segment that Nike is currently expanding is the professional sports arena with growing contracts with the NFL and other professional sporting leagues and teams across the world. Nike is the leader in the U. S. arket for all shoe and apparel sales and should continue to be the first choice of athletes who are looking to improve performance. Nike will also continue to make strides with advertising campaigns across Europe and India. D. Threats: i. Severe competition: The global shoe and apparel industry continues to experience fierce competition as major brands go head-to-head for competing for market share. According to Films on Demand video, Sports Shoe Wars, Adidas paid $1. 2 billion to retain the rights to the China Olympics for advertising rights at 23 of the 24 venues. The thought behind Adidas advertising campaign was â€Å"1. billion people with 2. 4 billion feet. † India is cle arly the next battle ground. Adidas is Nike’s most formidable competitor; the fight for market domination has spanned many decades and is publicly fought. Nike is the industry leader in the U. S. footwear and athletic apparel industry and has a strong brand portfolio (â€Å"Zacks Bull†, 2011). Adidas is known for making a solid, quality product which has historically missed consumer tastes. This was evident in a kid focus group conducted by Adidas in which kids were asked â€Å"if Adidas were at a party, where would it be? The kid’s responded â€Å"hanging around the keg† while â€Å"Nike would be with the girls. † (Stevenson, 2003) The belief at Adidas is Nike’s leadership position has been achieved solely through marketing, not through quality product performance. In a short film about the 2008 Olympic Games in China, Herbert Hainer, CEO of Adidas explains: I think if trying to find differences between the two companies, we’d have to say Adidas is more oriented towards product and performance and Nike more towards marketing. If they need hip hop culture to do that they will use it.But don’t think that Nike puts more into lifestyle than we do. We also communicate a great deal, like I said, we’re trying to do that in connection with the Olympic games†¦to win the people of China by saying we’re the ones who are helping your athletes. (Kirchhoff, 2009) In 2006, Adidas acquired Reebok to strengthen its position against Nike. The acquisition of Reebok led to control of 20% of the market as opposed to Nike which, at the time, had about a third of the $145 billion worldwide market. (Sorkin, Feder & Dash, 2005) The acquisition gave Adidas more leverage to compete for celebrity athlete endorsements. ii.The global economy is another threat that has already taken hold with a clear slowdown in worldwide shoe and apparel sales over the past few years. While the economy continues to be a proble m, a clear threat to Nike remains the volatility of third world governments where much of the materials and manufacturing is completed. E. How do Nike’s strengths reinforce their opportunities? Being well capitalized, Nike is in a position to take advantage of the professional sports organizations and teams target market. Many of these teams are recognized around the world and the Nike swoosh will be prominently displayed on their uniforms.Strong barriers to entry allow Nike to focus on their current competition with few to no disruptive technologies introduced by other companies in the shoe or apparel market. F. How do Nike’s weaknesses relate to their threats? Outsourcing manufacturing is a company decision they are comfortable with as they have done this for several decades now. The main benefit behind the outsourcing is expense reduction, and ability to focus on core competencies. However, along with these expense reductions comes human rights scrutiny that tends t o follow Nike wherever they go. A good reputation takes a long time to build and a short time to lose.But, they have made similar strides in the past with environmental groups and now will not allow harmful substances to be used for research and development there environmental groups recognize their environmental corporate culture and have worked closely with Nike over a period of 14 years to create these environmental values within the company. (Kirchhoff, A. (Director) (2009). ————————————————- V. Nike’s Value Chain Make, move, sell, use, reuse, plan, and design. A. Make: Since 1995 Nike has reduced petroleum based solvents used to manufacture shoes by 96%.Nike also created a new rubber that targets the reduction of the most toxic chemicals and shared the formula with the entire industry. The Nike â€Å"make† portion of the value chain employs 1,000,000 wor kers in 50 countries. The have also conserved enough materials in the last 5 years to produce an additional 15 million pairs of shoes. B. Move: Since 1995 Nike has used 100% recycled cardboard for shoe boxes. Clothing is also made from a lighter material which allows for less water usage in cleaning and it dries faster saving energy and allowing for larger drying loads in the process.Nike has 23 distribution centers located around the world and is working with logistics partners to reduce the footprint created in shipping and packaging of products. C. Sell: From June 2010 to January 2012 Nike employees donated 17,207 hours for community projects just in their North America retail stores. The employees completed 543 different projects that targeted youth sports. Approximately 219,000 plastic shopping bags were saved by the retail team in Australia in one year. With the plastic bag savings they began to charge an additional 10 cent fee and all proceeds from this fee were donated to lo cal youth sporting programs.This program resulted in a 55% reduction in plastic bag usage from the previous year and generated $26,000 for youth athletic programs. D. Use: In 2006 Nike did a study to find out where the most CO2 was being generated during the lifecycle of a typical pair of shoes. The study showed that 46% of these emissions came from the washing and drying. To further the study Nike came up with a 39% reduction in energy use simply by washing in cold water. This study was performed in an effort to reduce the carbon footprint and clothing now comes with instructions to use cold water and dry on a line instead of a dryer where possible.This cleaning method will also extend the life of the clothing. E. Reuse: Packaging accounts for up to 22% of the waste in the Nike value chain. Since 1995 all shoe boxes have been made from 100% recycled materials. In every square yard of school playground â€Å"play top† rubber there are approximately 40 pairs of grinded up shoe s where the rubber has been recycled. Nick also incorporates fiber into their Hyper Elite Platinum shorts that is made from 100% recycled polyester. The recycling of shoes has reached 25 million pairs collected globally since 1990. Nike’s goal is to â€Å"weave yesterday’s products back into tomorrow’s value chain. F. Plan: In 2010, Nike founded the Green Xchange with several other companies in an attempt at open innovation with other businesses. This Green Xchange is used to share intellectual property and conserve the planet’s resources and climate. In 2011 nearly 500 tons of waste was composted from the Nike headquarters and approximately 1. 6 million pound of waste was recycled. Those 500 tons equals about 65% of the total waste. Business travel has also been reduced to 3% of past travel requirements. Nike also focuses on minority owned businesses. G. Design: Each year over 16,000 materials are used in various products each year.Each pair of shoes co ntains about 30 different materials alone. Because so many different materials are used Nike has come up with â€Å"materials index† that measures the impact of each material in four areas. These areas include energy, chemistry, water, and waste. In 2010 15 million T-shirts were made using organic cotton that was grown without the use of fertilizers, defoliants, or pesticides. Nike has evaluated over 80,000 different to measure their environmental impact and typically uses 6 that make up most of their materials volume. These 6 items are polyester, rubber, cotton, synthetic leather, and leather and EVA foam.Finally, through planning and reducing their waste stream approximately 280,000,000 plastic bottles have been saved from landfills and used in polyester textiles. â€Å"In 2011, more than 31. 5 million Nike garments contained at least some recycled polyester fiber. † (Nike value chain, 2012) —————————â₠¬â€Ã¢â‚¬â€Ã¢â‚¬â€Ã¢â‚¬â€Ã¢â‚¬â€Ã¢â‚¬â€Ã¢â‚¬â€- ————————————————- ————————————————- ————————————————- ————————————————- ————————————————- ———————————————— ————————————————- VI. Porters 5 Competitive Forces à ¢â‚¬â€Ã¢â‚¬â€Ã¢â‚¬â€Ã¢â‚¬â€Ã¢â‚¬â€Ã¢â‚¬â€Ã¢â‚¬â€Ã¢â‚¬â€Ã¢â‚¬â€Ã¢â‚¬â€Ã¢â‚¬â€Ã¢â‚¬â€Ã¢â‚¬â€Ã¢â‚¬â€Ã¢â‚¬â€Ã¢â‚¬â€- The Organization (Format taken from Quick MBA, 2010) ————————————————- VII. Organization A. How the Culture Supports Innovation and Success An organization’s culture is typically defined by management at the top. Without a doubt, Nike’s legendary former CEO and Co-Founder, Phil Knight, was influential at developing a culture of innovation. His odd management style inspired employees to make their own decisions.He deliberately didn’t respond to questions or offered a vague nod. His executives became adept at interpreting his lack of response or nods as freedom to do their own problem solving and innovate. Most employees, like Tinker Hatfield, VP of Innovation, considered silence a yes to move forward. (Roth, 2005) Parker has c ommented that Knight has â€Å"always given me incredible freedom in my roles. † (Birchall, 2007, para 8) Whether intentional or unintentional, Knight personally provided critical ingredients for cultivating and nurturing a culture of creativity and innovation.The competitive spirit is deeply ingrained in the culture and employees are driven to succeed. The highly-popular slogan â€Å"Just Do It† is an internally-embraced philosophy that captures this competitive spirit. Nike’s culture gives employees the opportunity to accomplish, occasionally fail and learn from mistakes. Repeated failure faces punishment. (Jagersma, 2003) Curiosity is considered key to success and it is expected that employees will maintain a level of curiosity or risk failure.According to author Fields, the former CMO of Nike, Scott Bed bury, was quoted in the book Chasing Cool: Standing Out in Today's Cluttered Marketplace, as saying: â€Å"If you were the head of Nike Basketball, you damn well better know what's going on in the minds of young basketball players–the music they listen to, their vernacular, how they define success, what they fear, what they dream. The bulk of it is just about getting out there and wandering around. And anybody in the marketing group at Nike was penalized, if not put into early retirement, if they didn't get out there, if they weren't continually curious. (Fields, 2007) Hero worship is also deeply ingrained in the culture. Buildings on the Beaverton, OR campus bear the names of image-building power athletes. (Rapaport, 2002) To evoke the spirit of innovation through organizational history, storytelling about heroes and heritage is a critical part of Nike’s corporate culture. (Ransdell, 1999) Ekins, Nike’s official company storytellers, sport a swoosh tattoo on their ankle and evangelize about the Nike brand and its sports technology. (â€Å"Remarkable†, 2010) Today, the management style of Mark Parker, CEO, c ontinues to nurture innovation and keeps the channels for creativity open.He does not shut people down in meetings and prefers to let people share what they’re working on, even if a project will not get a green light. (McGirt, 2010) B. Organizational Structure for Optimal Alignment with Customer Markets In the mid-2000s, the company moved from a product-based structure to a customer-focused organization with categories like women’s fitness, running, and basketball. This allowed Nike to follow the greatest opportunities and to develop communities of shared interest both internally and externally. (Birchall, 2007) In 2009, another restructure aligned the brand by six new geographies hich allowed Nike to get closer to the customer, reduce management layers and increase the speed of decision making. (â€Å"Nike, Inc. Announces,† 2009) This structure allows Nike to more efficiently focus on the unique cultures of these sports, share knowledge, and inform the creative process. C. Breaking into New Sports with Independent Teams Breaking into new sports markets is a strategic endeavor for Nike. The company sets up independent entities and forms teams with external talent to allow it to be as agile as needed for success.To break into the skate market, the company brought former head of Nike’s upstart soccer division out of retirement. The division was set up as an independent unit with 11 employees who were all skaters from other parts of the industry. The skate team spoke to consumers for two years before it offered its first products exclusively to skate stores on short-runs and has since captured market share. (Stone, 2004) Golf is another market which required a different approach to break into it. The golf unit was formally separated from the rest of the company on its balance sheet.A 12-handicap golfer and long-time employee, Bob Wood, was asked to head the division, and other executives were brought on board from the industry. Since s electing Tiger Woods to represent their line of products, Nike has captured market share in golf. (Stone, 2004) ————————————————- VIII. Innovation Process A. Innovation Kitchen and Sources for Innovation Inspiration The Innovation Kitchen is a think tank within Nike’s headquarters where innovative technology and other special projects are invented by its 125-person research team.Tinker Hatfield, VP Innovation and Special Projects, leads the team. He is a famed designer of Nike’s most popular and innovative designs, including the Air Jordan, and is regarded as the keeper of the founder’s legacy of innovation. As Hatfield explains, the Kitchen is separated from the rest of the organization: â€Å"We're not so much tied into the sales of shoes. We're here to improve athletic performance. † (Rapaport, 2002, para 25) While casual visits by the CEO ar e common, direction for their work does not come from above.It is guided by a philosophy established by Knight: â€Å"It’s really risky not to take risk. † (Brettman, 2011b, para 7) The research team is free to explore as many ideas as they can. Behind Nike’s core competency in innovation is a finely-tuned integration of learning with creativity. (Stonehouse & Minocha, 2008) Hatfield believes what designers draw or design is a culmination of everything he or she has seen or done in life at that point. (Longeville, 2006) To Hatfield, internal ideas generated from sources such as focus groups are generated in false environments, thus not the preferred source for ideas. Eckoff, 2007) Instead, creativity and inspiration is regularly sought out from a wide variety of external influences. The insights provoke new ways of thinking and innovating. i. Athletes: For Nike, design is rooted in the belief that form follows function. Top athletes have been – and wi ll continue to be – the primary source of design inspiration. According to Parker, â€Å"what we learn from them is who we are. † (McGirt, 2010, para 8) Nike employs pro athletes, either with the company or via sports marketing contracts, to evaluate and weigh in on shoe design and development from a performance perspective. Datamonitor, 2012) They are frequent visitors to the Nike Sports Research Lab, where biomechanics experts study how to enhance their performance using cutting-edge sports technology and equipment. (McGirt, 2010) How the R&D team of scientists analyzes the results sets Nike apart. According to Mario Lafortune, Director of Nike’s R&D Lab: We have developed an expertise in interpreting the data for designing footwear. How you interpret data to derive footwear criteria is really a level of expertise that very few people have. Holloway, 2004, para 7) Inspired design originates not just from input on functionality, but as Hatfield explains : You have to spend time getting to know an athlete, his motivations and his life. Understand his needs and his wants. The real fun comes in the end when you make observations that have real meaning. (â€Å"Interview: Tinker Hatfield ,† n. d. , para 14) ii. Customers: Lifestyle Trends: Nike understands that to grow, recognizing new customer needs and offering solutions is critical. (Patnaik, 2005) Nike’s ability to apply outside the box thinking to existing solutions has proven successful.For example, by looking at the lifestyle of the runner, Nike teamed with Apple to create Nike+, a digital sports kit comprising a sensor that attaches to a running shoe with a wireless receiver which connects to the iPod. The information tracked by the sensor sends information to the iPod for uploading and tracking progress on www. nikeplus. com, then shared on Facebook and Twitter to connect with other runner communities. For the Nike+ customer, the exercise experience has extended b eyond a pair of running shoes. As of 2010, 2. million kits were sold and due to that success, the kit has been expanded into other athletic activities, such as gym workouts. (Ofek & Wathieu, 2010) iii. Deep Dives: To stay ahead of consumer trends, Nike designers regularly seek inspiration through intense immersion into subcultural experiences, or Deep Dives. According to John Hoke III, Nike’s global creative director of footwear design, the purpose of Deep Dives is â€Å"to interpret, translate and try to make new connections†. Deep Dive cultural explorations have included American car culture, Palm Springs mid-20th-century design, inner-city hip-hop music and origami.Other lighter immersions such as trips to the zoo to sketch animal feet are part of this process as well. The idea is to infuse thinking with new design and aesthetic possibilities and inform new ways of connecting with their target customer. (Rapaport, 2002) iv. Art, Artists and Buildings: The work o f street artists have served as sources of inspiration, both in adding aesthetic appeal to shoes and in helping Nike establish credibility with hard-to-reach audiences. Parker has developed a network of artists as a long time art collector.He tapped his graffiti artist network to help establish authenticity in the hard-to-break-into skate market. Mr. Cartoon, a Los Angeles graffiti-and-tattoo-design star, was asked to design limited-edition versions of classic Nike shoes and was given a platform to hold special events advocating design self-discovery to Latino youth. This demonstrated Nike’s ability to understand and connect with this unique culture. The shoes are now collector’s items. Parker continues to stay connected with his artist network as he considers them as influencers of influencers in pop culture. Birchall, 2007) After travelling to Paris to see Pompidou Centre, a building characterized by exposed mechanical systems and bright colors, Hatfield suggested th e air bag of the shoe be exposed and visible through the sole. His idea was initially met with resistance from many. The Head of Marketing for Running couldn’t figure out how this shoe could be sold. (Longeville, 2006) Now, the Air Max line of shoes has been wildly successful. B. Experts, Incubation, and Collaborations Other external resources are tapped as part of Nike’s innovation process.Research committees and advisory boards with experts such as athletes, coaches, trainers, equipment managers, orthopedists, and podiatrists are frequently consulted with. (Datamonitor, 2012) Nike also sets up venture capital offshoots to explore new ideas. In 2011, the company set up the Sustainable Business & Innovation Lab to back other start-up ventures focused on alternative energies, efficient manufacturing practices, and companies that promote healthy lifestyles. (Kharif & Townsend, 2011) Other groups are tasked with collaborations.Parker was concerned about Nike innov ation being too insolated and set up Explore to pursue long-range innovation possibilities with academics, inventors and other companies. (Exon, 2002) One of Explore’s successes was the collaboration with Apple to produce Nike+. (Birchall, 2007) Analysts believe that a 55% growth in membership for Nike+ was responsible for an increase in sales in the running division up 30%, to $2. 8 billion. (Cendrowski, 2012) ————————————————- IX. From Idea to Commercial Product Innovation at Nike is clearly a bottom-up process.After ideas are generated, the labs have what is generally referred to as a peer review. At this time, research ideas are shared internally with lab peers and the lab director only. If the lab director believes the idea is worth pursuing, resources are allocated by the lab to investigate it further. (Rodrigues, R. , personal communication, June 10, 2012) At the investigation stage, external knowledge is gathered. Patents are researched to ensure no patent infringement. If the idea seems feasible based on information gathered in the steps in this process, the idea is developed further into a prototype and patents are filed. (Rodrigues, R. personal communication, June 10, 2012) The lab funds development of a prototype in what is generally known in engineering as the laboratory phase. About once a month, senior executives are invited to review prototypes and vet them against Nike’s mission statement and corporate goals. If a prototype is accepted, the idea could potentially be pitched to the board of directors. (Rodrigues, R. , personal communication, June 10, 2012) As an example, in the mid-80s, Parker, product designer at the time, was working on a side project visible air in which the sole cushioning technology would be exposed so the customer could see it.He was invited by Phil Knight to present his prototype to the board. (Mc Girt, 2010) At this stage, the lab might also produce a white paper with â€Å"ideas on feasibility† which is usually written for manufacturing and division heads of product lines. It may be unclear at this point which product line this technology might be used in, and there is most likely internal competition as to which division might get it. (Rodrigues, R. , personal communication, June 10, 2012) The visible air technology spurred the Air Max shoe line for running, basketball and cross-training.In Nike’s bi-annual Concept Debut, the review committee (CEO and heads of global footwear design) reviews all designs for products due to hit the market in the next18 months. Details of each prototype are discussed and sketches critiqued. If a product passes review, the company intends to commercialize and produce it and will fund it. All the regions are brought on board to determine the go-to-market strategy. Marketing is involved at this stage. (â€Å"Online extra: Chaos,à ¢â‚¬  2007) From there, the product is transferred to manufacturing for production.No doubt, Nike’s lab has a close relationship manufacturing suppliers and they are involved much earlier in product development than this stage. For example, the Flyknit due to hit stores July 2012 is made from a knitting process which weaves an entire shoe upper in one piece. With 35 fewer pieces to assemble, this is a revolutionary approach to shoe production as it eliminates the cutting and stitching process, translating to less labor and higher profit margins for Nike. (Townsend, 2012) Manufacturing most certainly played a role in the product development process. ———————————————— X. Product Introduction to the Market A. Marketing Strategy As one of Nike’s core competencies, marketing plays a pivotal role in the company’s success. Historically, Nike has utilized an a lmost formulaic, two-prong approach to marketing – elite athlete endorsements and establishment of an emotional connection with their customer. Some of the greatest elite athletes have been paid by Nike to help design, develop, and sell merchandise through endorsements.Tiger Woods was signed in 1996 and by 2001, Nike’s market share in golf jumped from one to six percent, or $50 million. (Cummings, 2001) Instead of focusing on the product, Nike’s advertising strategy seeks to establish an emotional connection with the customer by setting a mood. Just after Nike’s revenues fell 22% in 1986, Nike launched its first national ad campaign which featured the song Revolution and intertwined clips of elite Nike athletes with clips of everyday people. The underlying message was athletes prefer Nike, buy Nike and you can play as good as them. Lane, 1996) By 1988, revenues rebounded to $1. 2B and by 1989; the company regained its leadership position, earning $1. 7B i n revenue. (Jorgensen, 1994) However, as Nike’s total marketing budget has climbed, it’s spending in U. S. TV and print advertising has dropped by 40% in the past three years signaling a marketing strategy shift. In 2010, Nike launched Nike Digital Sport, a new division aimed at developing devices and technologies for users to track personal sports statistics. Now, customer data can be mined and online communities established, placing Nike where the customer is. Cendrowski, 2012) While initial attempts have not been so successful, true to Nike’s innovation process, the company integrates its knowledge into new tactics and continues try new approaches. B. Event Pacing and Limited-Edition Products Nike has been known to utilize two strategies to stimulate demand: event-timed product releases and limited-edition product. Nike both releases new products to coincide with big sports events – and also delays them. Earlier in 2012, the Foamposite One Galaxy glow- in-the-dark shoes were released to coincide with the NBA All-Star game in Orlando.This year, new home and away soccer apparel in the team colors for FC Internazionale were released in time for the 2012-2013 Milan soccer seasons. (Nike, Inc. , 2012b) In 2007, Nike delayed the release of the new Michael Vick shoe when Michael Vick was caught in a dog fighting scandal. (Briggs, 2007) When coupled with limited-run production, marketing hype has led to success, if not violence. Nike makes it known that the Jordan XIs — Jordan's most sought-after shoe – are released once a year as a limited edition.The December 2009 holiday season release of Air Jordan XI Concords caused violence and a stabbing. (Hill, 2011) But at more than $1 billion in sales, the Jordan brand now makes up roughly 5 percent of Nike’s overall revenues. (Rovell, 2009) ————————————————- XI. I ntegrated Strategy: Sustainability and Innovation The integration of sustainability and innovation as a value-creator forms the core of Nike’s new strategy. (Brettman, 2011a) Nike believes corporate social responsibility extends beyond the walls of their headquarters to the industry and society.The goal is to innovate systematically throughout all businesses processes and to affect change industry-wide for the good of society. Nike’s troubles in China led to heightened awareness about corporate responsibility and the company’s impact on society. A. Nike and China Nike and several other name brand organizations have had trouble with child labor issues. There have been allegations of child labor and horrid working conditions. According to Irene Alfred from Nike slave labor† Nike is having difficulties with the publicity it is receiving about its labor practices in China, South Korea, Indonesia, and Vietnam.In China, employees for Nike work twelve hour shifts for several days a week. Their wages are as low as sixteen cents an hour there is no union†. Nike is working on improving conditions for its international employee’s in1998 Mr. Knight stated,† Public speeches regarding his plan for the labor conditions to be brought up to standards. I feel that this is a great step to take in showing that Nike does actually care about its employees and the conditions they work in. Finding contractors that follow the health and safety codes and staying away from the corrupt government involved contractors.Incorporating interest in the educational systems where they are involved and showing the communities you operate in that you do care about their welfare status. Phil Knight did the right thing by addressing the media about theses speculations and taking action and getting involved with the citizens is a great first step. In addition, by going into these very poor countries that are plagued with hunger, poverty and illiteracy, Ni ke is giving these people a second chance at life by providing them with jobs to provide their families with meals and a chance to get an education and break the cycle of illiteracy and poverty in these communities.B. Green Xchange, Considered Design and Considered Design Index Now, Nike is driven to affect systemic change through open collaboration and designing products with sustainable design choices. In 2010, Nike launched the GreenXchange, a web-based collaborative network promoting the creation and adoption of technologies for new sustainability models and innovation. (Albanese, 2012) Nike’s new design philosophy, Considered Design, utilizes sustainable design choices at the start of the creative process to innovatively eliminate design and development waste.Sustainability is measured using metrics in their Considered Design Index. Nike intends to share this Index to create an industry-wide scale. (Nike, Inc. , 2012a) C. Impact on Corporate Goals/Strategy As Nike contin ues to integrate sustainability goals into their innovation processes, the company continues to raise their performance expectations. In May 2012, Nike announced new sustainability performance targets, both short and long term, and a company-wide commitment to further integrate sustainability principles into its innovation processes, governance and portfolios. â€Å"Nike, Inc. Introduces,† 2012) ————————————————- XII. Conclusion Nike’s intense passion for and focus on improving athletic performance has been the driver behind the company’s ability to establish a leadership position in the market. The competitive culture is sharply focused on winning in whatever endeavor the company endures, and their innovation processes support this Just Do It mentality. Their ability to finely integrate creativity and learning forms the core of their innovation proces s.Their curious culture uses external knowledge gained to innovate for the athlete and make an emotional connection with their customer through marketing. The company continuously refines their approach, as evidenced in their new marketing strategy, and as they continue set new challenges, Nike positions itself to defend their leadership position. ————————————————- References Albanese, M. (2012, Feb 06). How she leads: Hannah jones of nike. Greenbiz. com, Retrieved from http://www. greenbiz. com/blog/2012/02/06/how-she-leads-hannah-jones-nike Alfred, I. Jan 2003). Slave Labor. Retrieved on May 30, 2012 from http://from http://ihscslnews. org/view_article. php? id=121 Birchall, J. (2007, Mar 18). The man who made a career out of cool. Financial Times. Retrieved from http://www. ft. com Brettman, A. (2011a, Oct 04). Hannah jones of nike delivers message of doom and hope at g ogreen ’11 conference. Oregon Live. Retrieved from http://www. oregonlive. com/playbooks-profits/index. ssf/2011/10/hannah_jones_of_nike_delivers. html Brettman, A. (2011b, May 11). Nike designer describes life inside the innovation kitchen. [Blog Post].From http://blog. oregonlive. com/playbooksandprofits/2011/05/nike_designer_describes_life_i. html Briggs, B. (2007, Jul 18). NFL megastar vick’s endorsements in danger. msnbc. com. Retrieved on July 31, 2012 from http://www. msnbc. msn. com/id/19834805/ns/business-us_business/t/nfl-megastar-vicks-endorsements-danger/#. UCH28qNf9Mg Cendrowski, S. (2012, Feb 13). Nike's new marketing mojo. CNN Money, Retrieved from http://management. fortune. cnn. com/2012/02/13/nike-digital-marketing/ Cummings, B. (2001). Star power. Sales and Marketing Management, 153(4), 52-59. Retrieved from

JAM session topics Essay

Audio-Video mixing is an important aspect of cinematography.Most videos such as movies and sitcoms have several segments devoid of any speech.Adding carefully chosen music to such segments conveys emotions such as joy,tension or melancholy. In a typically professional video production,skilled audio-mixing artists aesthetically add appropriate audio to the given video shot. This process is tedious, time-consuming and expensive. The PIVOT VECTOR SPACE APPROACH in audio mixing is a novel technique that automatically picks the best audio clip (from the available database) to mix with the given video shot.This technique uses a pivot vector space mixing framework to incorporate the artistic heuristics for mixing audio with video. This technique eliminates the need for professional audio mixing artists and hence it is not expensive.It also saves time and is very convenient. In today’s era, significant advances are happening constantly in the field of Information Technology. The development in the IT related fields such as multimedia is extremely vast. This is evident with the release of a variety of multimedia products such as mobile handsets, portable MP3 players, digital video camcorders, handicams etc. Hence, certain activities such as production of home videos is easy due to products such as handicams, digital video camcorders etc. Such a scenario was not there a decade ago ,since no such products were available in the market. As a result production of home videos is not possible since it was reserved completely for professional video artists. So in today’s world, a large  amount of home videos are being made and the number of amateur and home video enthusiasts is very large.A home video artist can never match the aesthetic capabilities of a professional audio mixing artist. However employing a professional mixing artist to develop home video is not feasible as it is expensive, tedious and time consuming. Introduction The PIVOT VECTOR SPACE APPROACH is a novel technique of audio-video mixing which automatically selects the best audio clip from the available database, to be mixed with the given video shot. Till the development of this technique, audio-video mixing is a process that could be done only by professional audio-mixing artists. However employing these artists is very expensive and is not feasible for home video mixing. Besides, the process is  time-consuming and tedious.In today’s era, significant advances are happening constantly in the field of Information Technology. The development in the IT related fields such as multimedia is extremely vast. This is evident with the release of a variety of multimedia products such as mobile handsets, portable MP3 players, digital video camcorders, handicams etc. Hence, certain activities such as production of home videos is easy due to products such as handicams, digital video camcorders etc. Such a scenario was not there a decade ago ,since no such products were available in the market. As a result production of home videos is not possible since it was reserved completely for professional video artists.So in today’s world, a large amount of home videos are being made and the number of amateur and home video enthusiasts is very large.A home video artist can never match the aesthetic capabilities of a professional audio mixing artist. However employing a professional mixing artist to develop home video is not feasible as it is expensive, tedious and time consuming. Fig(1) PivotVectorRepresentation AESTHETIC ASPECTS Movies comprise images (still or moving) ;graphic traces(texts and signs);recorded speech, music, and noises; and sound effects. The different roles of music in movies can be categorized into :– Setting the scene(create atmosphere of time and place) Adding emotional meaning , Serving as a background filler, Creating continuity across shots or scenes, and  Emphasizing climaxes(alert the viewer to climaxes and emotional points of scenes).  The links between music and moving images are extremely important, and the juxtaposition of such elements must be carried out according to some aesthetic rules. The scientist Zettl explicitly defined such rules in the form of a table, presenting the features of moving images that match the features of music. Zettl based these proposed mixing rules on the following aspects:– Tonal matching(related to the emotional meaning defined by  Copland) Structural matching(related to emotional meaning and emphasizing climaxes defined by Copland) Thematic matching(related to setting the scene as defined by Copland) Historical-geographical matching(related to setting the scene as defined by Copland) In the following TABLE ,we summarize the work of Zettl by presenting aesthetic features that correspond in video and music. The table also indicates extractable features because many video and audio features defined by Zettl are high level perceptual features and can’t be extracted by the state of the art in computational media aesthetics. VIDEO AESTHETIC FEATURES The table shows, from the cinematic point of view,a set of attributed features(such as color and motion) required to describe videos.The computations for extracting aesthetic attributed features from low-level video features occur at the video shot granularity. Because some attributed features are based on still images(such as high light falloff),we compute them on the key frame of a video shot. We try to optimize the trade-off in accuracy and computational efficiency among the competing extraction methods. Also, even though we assume that the videos considered come in the MPEG format(widely used by several home video camcorders),the features exist independently of a particular representation format. The important video aesthetic features are as follows:– LIGHT FALLOFF : Light falloff refers to the brightness contrast between the light and shadow sides of an object and the rate of change from light to shadow. If the brightness contrast between the lighted side of an object and the attached shadow is high, the frame has fast falloff. This means the illuminated side  is relatively bright and the attached shadow is quite dense and dark. If the contrast is low, the resulting falloff is considered slow. No falloff(or extremely low falloff) means that the object is lighted equally on all sides. COLOR FEATURES The color features extracted from a video shot consists of four features:- Saturation Hue Brightness Energy MOTION VECTORS To measure the video segment’s motion intensity, we use descriptors. They describe a set of automatically extractable descriptors of motion activities, which are computed from the MPEG motion vectors and can capture the intensity of a video shot’s motion activity. Here we use the max2 descriptor, which discards 10 percent of the motion vectors to filter out spurious vectors or very small objects AUDIO AESTHETIC FEATURES Music perception is an extremely complex psycho-acoustical phenomenon that is not well understood. So instead of directly extracting the music’s perceptual features, we can use the low-level signal features of audio clips, which can provide clues on how to estimate the numerous perceptual features. LOW-LEVEL FEATURES We described here the required basic features that are extracted from an audio excerpt. Spectral centroid The spectral centroid is commonly associated with the measure of a sound’s brightness.We obtain this measure by evaluating the center of gravity using the frequency and magnitude information of Fourier transforms.The individual centroid C(n) of a spectral frame is the average frequency weighted by the  amplitude ,divided by the sum of the amplitude. Zerocrossing In the context of discrete-time signals, a zero crossing is said to occur if two successive samples have opposite signs. The rate at which Zero crossings occur is a simple measure of the frequency content of the signal.This is particularly true of the narrowband signals. Because audio signals might include both narrowband and broadband signals, the interpretation of the average zero-crossing rate is less precise. However, we can still obtain rough estimates of the spectral properties using a representation on the short-time average zero-crossing rate. Volume The volume distribution of audio clips reveals the signal magnitude’s temporal variation. It represents the subjective measure, which depends on the human listener’s frequency response. Normally volume is approximated by the root mean square value of the signal magnitude within each frame. VDR(v)=[max(V)-min(v)]/max(V) PERCEPTUAL FEATURES EXTRACTION Dynamics Dynamics refers to the volume of musical sound related to the music’s loudness or softness, which is always a relative indication, dependent on the context. Tempo features One of the most important features that makes the music flow unique and differentiates it from other types of audio signal is temporal organization(beat rate) Perceptual pitch feature Pitch perception plays an important role in human hearing, and the auditory system apparently assigns a pitch to anything that comes to its attention. ADVANTAGES Before the development of the PIVOT VECTOR SPACE APPROACH IN AUDIO-VIDEO MIXING process can be carried out only by professional mixing artists. In today’s era the development in the field of MULTIMEDIA technology is so vast as this can be seen with the releases of a number of multimedia products in the market. Products such as Digital video camcorders, Handicams greatly helped even normal home users to produce their own video. However, employing professional audio-mixing artists is not feasible since it is expensive, time-consuming and tedious. The Pivot vector space approach enables all the home video users and amateur video enthusiasts to give a professional look and feel to their videos. This technique also eliminates the need for professional mixing artists and hence saves cost. Besides, it is not time-consuming. Since this approach is fully automatic as it automatically selects the best audio clip (available from the given database) to be mixed with the given video shot ,the user need not worry about his aesthetic capabilities in selecting the audio clip. The Pivot vector space approach enables all the home video users and amateur video enthusiasts to give a professional look and feel to their videos. This technique also eliminates the need for professional mixing artists and hence saves cost. Besides, it is not time-consuming. Since this approach is fully automatic as it automatically selects the best audio clip (available from the given database) to be mixed with the given video shot ,the user need not worry about his aesthetic capabilities in selecting the audio clip. Fig(4): Application of Audio Video Mixing. APPLICATIONS In today’s INFORMATION TECHNOLOGY era ,the advances in the various IT fields such as MULTIMEDIA,NETWORKING etc is very fast.Newer and better technologies arise as each day passes. This is evident with the release of a number of Technology packed products such as portable MP3 players,digital cameras,digital video camcorders,Handicams,Mobile handsets etc. Before the advent of such technologies, activities such as Production of videos etc could be done only by professional video artists. However in today’s era,with the releases of products such as Handicams,Digital video camcorders;production of videos is easy for all the home video users and amateur video enthusiasts.As a result, a large amount of home video footage is being produced now. The PIVOT VECTOR SPACE APPROACH is a novel technique for these users since it is able to provide a professional look and feel to these videos.It eliminates the need for professional mixing artists and hence cuts down the cost ,time and labour involved.Hence,the demand for such a technique will be only increasing in the coming years .This technique will definitely have a great impact on the IT market today. CONCLUSION The PIVOT VECTOR SPACE APPROACH is a new dimension in the field of AUDIO-VIDEO mixing. Before the advent of this technology, audio-video mixing was a process carried out only by professional mixing artists. However, this process is expensive, tedious and time-consuming. This entire scenario changed with the emergence of the PIVOT VECTOR SPACE approach. Since this technique is fully Automatic, it enabled a home video user to provide a professional look and feel to his video. This technique also eliminates the need for professional mixing artists, thereby significantly reducing the cost, time and labour involved. In today’s era,a large amount of home video footage is being produced due to products such as Digital video camcorders, Handicams etc.Hence,this technique will be of great use to all the amateur video enthusiasts and home video users. REFERENCES IEEE Multimedia journal (Computational Media Aesthetics) CHIP magazine DIGIT magazine http://computer.org/multimedia/mu2003/u2toc.htm http://www.pcmag.com

The Current Tools for Diplomacy and Peacekeeping Coursework

The Current Tools for Diplomacy and Peacekeeping - Coursework Example The focus has been on occasional operations involving peacemaking and humanitarian intervention instead of wars. In Africa, several peacekeeping bodies have been made such as African Union`s Peace and Security Council, working on conflict prevention and preventive diplomacy. Nearly half of the UN peacekeeping operations in Africa are in Sub-Saharan Africa, the objectives of which are to promote stability in several regions of Africa, to stop renewed violence in Congo and other such peacemaking objectives. The US presidential statement focused on dealing with the root causes of violence in Africa. It also focused on the importance of structural and operational strategies for peacemaking in the region. It has been observed that Africa has fully supported the efforts of the UN in the promotion of peace and stability in the country through these diplomatic tools. The dominant powers have co-operated by providing security in exchange for resource supplements. Several peacemaking missions have already been completed such as those in Somalia, Rwanda, Liberia etc and several others are in process. The  US has used mediation strategies such as those in Angola and Namibia agreements and other indirect mediation in Liberia etc. Equitable power balance has been promoted throughout Africa. Central state power has also been reduced to give more autonomy to political groups and parties. The Rwandan genocide was one of the most devastating massacres of the world. Nearly 800,000 people were killed without any reason. The killing of these 800,000 people went unchallenged by the global community as important decision makers ignored such a big massacre. The United Nations sent a group of peacemakers for what seemed to be a plain and straightforward mission.

Evolution of the World Bank Case Study Example | Topics and Well Written Essays - 2500 words

Evolution of the World Bank - Case Study Example The World Bank is a group of five closely associated international organizations responsible for providing finance and advice to countries for the purposes of economic development and eliminating poverty. Its five agencies are: International Bank for Reconstruction and Development (IBRD); International Finance Corporation (IFC); International Development Association (IDA); Multilateral Investment Guarantee Agency (MIGA); and International Centre for Settlement of Investment Disputes (ICSID). The World Bank's activities are particularly focused on economically backward developing countries. These activities are in fields such as agriculture and rural development (e.g. irrigation, rural services), human development (e.g. education, health), infrastructure (e.g. roads, urban regeneration, electricity), governance (e.g. anti-corruption, legal institutions development) and environmental protection (e.g. pollution reduction, establishing and enforcing regulations). Each of these organizati ons has their own aims and objectives. The International Bank for Reconstruction and Development (IBRD) aims to reduce poverty in middle-income and creditworthy poorer countries by promoting sustainable development through loans, guarantees, risk management products, and analytical and advisory services. The IBRD and IDA provide loans at preferential rates to member countries, as well as grants to the poorest countries for developmental activities. Most of the times loans or grants for specific projects that may result in improvement of policy changes. For instance, loans to improve coastal environmental management that may be linked to development of new environmental institutions at national and local levels and to implementation of new regulations to limit pollution. The main activities of the IFC and MIGA include investment in the private sector and capitalizing insurance respectively (Wikipedia, 2007a). The IBRD was established in 1944 as the original institution of the World Bank Group. It is structured like a cooperative that is owned and operated for the benefit of its'185 member countries (web.worldbank.org, 2007). IBRD raises most of its funds on the world's financial markets. In 1946 the Bank had an authorized capital of $10 bi11ion, worth about 20 times as much today. However, all through its development it has been singularly garnered more controversy and criticism than any other international financial or development institution. In 1993 the Bank's total callable capital was almost $166 billion, though of that only $10.53 was paid in (Rich, 1994). The income that IBRD has been generated from the time of its inception has allowed it to fund development activities and to ensure its financial strength. As a result of this it is enabled to borrow at low cost and offer clients good borrowing terms (web.worldbank.org, 2007). From mid 1946 to mid 1986 the World Bank lent a total o f $160 billion for 4,000 different projects in around 100 countries, and has even more increased in the last few decades. By any reckoning the Bank's resources are huge (Hardy, N.D.). Till date IBRD has not suffered any losses

A-Level Law in Action Essay Example | Topics and Well Written Essays - 1250 words

A-Level Law in Action - Essay Example For instance, in R v Steane, the accused lent his services to the enemy, in order to protect his family from harm. Consequently, his conviction was set aside6. Â  On the other hand, indirect or oblique intent arises when the accused can foresee the outcome, as being highly probable, and the accused does not desire that outcome. In Hyam v DPP, the accused’s intention had been to terrify the victim and not to cause her death, when he set fire to her house. Their Lordships upheld the conviction for murder, as the accused could anticipate that his actions could result in death or grievous bodily harm7. Â  In the present problem, Bob with the intention of killing Alice exploded a petrol bomb. As a consequence, Alice lost her life. Bob caused her death intentionally.This constitutes, the crime of murder, and Bob will be accordingly held liable. Â  In Goodfellow, the accused was convicted of constructive manslaughter, for having caused the death of his family, while attempting to set his house on fire. It is important to note that he had no intention of causing the death of his family8. Â  Bob had claimed that it was not his intention to cause harm to anyone other than his wife, Alice. This is untenable, on account of the doctrine of transferred malice. The letter states that if an individual has the Mens rea to commit a specific offense against a particular person, and if that crime had been committed by that individual against some other person, then the Mens rea is transferred to the actual victim. This is borne out by the decision in R v Mitchell, wherein the accused had caused the death of an old woman, by striking an old man who fell on that old woman. The latter died subsequently, due to the complications that had arisen in her treatment.

Steven Spielbergs Schindlers List A Legend Essay

Steven Spielbergs Schindlers List A Legend - Essay Example In the film of Steven Spielberg, the story of the Holocaust was made into action. It went further to include other real life testimonies from survivors and witnesses of the historical event. Spielberg went into deeper facts through interviews and actual visitation of the places where mass murder supposedly occurred. This three-hour movie is styled differently. Unlike any other hit movies in the Hollywood, Schindler’s List is being filmed in documentary form. The actual events were portrayed in patches of scenes that came from real life experiences of those who knew better- the survivors and witnesses. Series and factions of the whole genocide story were being reduced into scenes from various perspectives. This reduction or miniaturization of the specific events is as much as part of the cataclysm of the Jews extermination plan of the Nazis. Various scenes were made into action depicting the experiences of the Jews under the Nazi rule. There are scenes of Jews transported in trains and held in forced labor camps, and scenes of families broken as men, women, children and old people were separated from each other. There are also scenes of people going into gas chambers being killed at once as gas fumes are being released with Jews being imprisoned inside the chambers. This series of events add up to the horrific totality of the genocide plan of the Nazis. These murders and life-exterminating events to stamp out the Jews lineage in the face of humanity were being made into reality by the actors directed by Spielberg.teven Spielberg. It takes a lot of various perspective of the Holocau st event to totally capture what really happened in the history. Replicas and literal imitations of the events were acted by chosen actors quite effectively. Supporting props and scenic settings as backgrounds helped in the total output scene on cameras. As the film is being shown as a documentary, the events do not limit to the world of the life of the protagonist alone. Although most part of the movie progressively follow the events that happened with Oskar Schindler, but the events does not limit to his experiences alone. Stories of various Jews were portrayed one by one to provide different perspective. Black and White â€Å"Schindler’s List† is a uniquely fabricated film done by the hands of the expert. Unlike Spielberg’s usual movies that are full of stunning and spectacular effects, with

Children's Fire Safety Programs in Edinburgh Term Paper - 1

Children's Fire Safety Programs in Edinburgh - Term Paper Example The first level of operational assurance that will be available will be based on the evaluation programs that will be implemented. The surveys that will take place after the programs can be considered and assessed for the short-term goals being met. If the retention levels of the fire hazard programs continue to improve and if the teacher responses are implemented, then it can be seen that the staff are providing the right level for the programs. Continuous innovation and the ability to meet the short-term goals will then provide a stronger basis for the programs and will become a measure of the operational assurance that is a part of the program. This will be furthered by the specific needs that are within the educational areas. Being able to meet these and receiving direct responses from the educational institutions will ensure that there is a higher level of quality that is being met.The operational assurance will then be followed by the understanding that the staff needs to meet the standards that were provided as a main resource in the beginning. Monitoring and mediation will be given to the staff to ensure that they continue to meet the standards that are expected with both the programs and inside the office. By doing this, there will be the ability to ensure that the staff continues to comply with the standards that have been set by past programs. There will also be the ability to ensure that the standards continue to be implemented while raising the standards to current issues that are a part of the community. This will be followed by the ability to create programs that are built from a combination of innovation and basic standards that are in compliance with the expected resources.

Buyer Behavior Essay Example | Topics and Well Written Essays - 2000 words

Buyer Behavior - Essay Example Various models of consumer behaviour have been developed over the years. The models reflect the different buying situations in which consumers find themselves. Factors influencing consumer behaviour must be considered as well as similar factors influencing the buying decisions in business to business transactions. An understanding of these factors and how they influence the buying decision are extremely important when putting together a selling strategy. Market research also plays an important part in helping to identify relevant facts about buyer behaviour (consumer or organizational) and provides all kinds of information which forms the basis of strategy formulation. A motive to make a certain purchase is an internal state of the purchase. While consumer behavior is observable, motives are psychological constructs that can only be inferred. Buying motives for consumer products may be classified as economic, emotional, product, and retail patronage. Some of the motives may be rational while others are emotional. To illustrate, economic motives include product durability or economy in use. Emotional motives might include romance, pleasure, or prestige. Product purchase motives might involve ease for making repairs or ease of installation. Patronage motives relate to variety for selection or promptness in delivery. Motives relate to perception. Motives come from the consumer's real self, self-image, ideal self, and looking-glass self. The way consumers envision the situation to themselves helps to shape their reactions or responses to marketers' appeals (Sharon, Boyle, 2004: 343). Consumer goals and needs are constantly changing in response to environmental conditions, interaction with others, and physical conditions. As individuals realize their goals, new objectives may be established. New levels of aspiration may surface. For example, if an individual loses ten pounds of weight another objective to lose an additional fifteen pounds may be established. Moreover, marketers need to be attuned to changing needs and goals. Automobile manufacturers have recognized the consumer's need for prestige or status. This need may be less important as some consumers seek safety or family enjoyment as reasons for purchasing a new car. Since many families own more than one motor vehicle, ownership of a Volvo sedan or station wagon, a pickup truck, and an economical used car for an adolescent might represent diverse needs. The reason consumers choose one brand over another may be vague and unknown to them. Why consumers choose one brand of refrigerator over another may be based on personal experience, an advertisement, a friend's comment, a salesperson's presentation, the location of the retailer for service or some other factor or combination thereof. Brand switching may occur as a result of changing needs, a dissatisfaction with the current brand used, or because a friend, relative, advertising campaign, an article in Consumer Reports, or other influence persuaded that consumer that a better benefit or value can be derived by switching brands. Marketers, by identifying and appealing to consumers' motives, can generate a positive environment for the sale of their products. A study of men depicted

The Author of Her Book by Anne Bradstreet Essay Example for Free

The Author of Her Book by Anne Bradstreet Essay The debate starts with an argument among two people, DeSean and Sole. Sole was trying to help DeSean through a spiritual crisis and trying to answer the question in such a way that it would have been treated if it were posed before Jesus, hence focusing on what Jesus might have done when found in the same situation. The theological debate for this argument is: â€Å"How do we reconcile the fact that Jesus Christ was fully God with the fact that Jesus was fully human? Christians believe that Jesus was fully man and God at the same time, formalized by the Council of Chalcedon in AD 451. Arianism believed by the Jehovah witness is that Jesus was the first and greatest creation of God. Muslims on the other hand simply believe Jesus is just a prophet of God, but in all most people believe in Jesus Christ’s divinity and humanity at the same time. A group holds Kenotic Christology which explains God had to empty himself to become fully human, thus God laid is omniscience and became fully man. Two essays which offered defense of the classical Christological position and defense of the kenotic Christological position The Classical view where some Theologians agreed that Jesus was at and the same time omnipresent yet spatially located omnipotent but limited in power. Some evangelicals believe that Jesus was fully God and fully human, and insist that he laid aside the use of is divine attributes in order to become a human, whiles retaining his divine holiness and love temporarily whiles slowly releasing his divine attributes. While the Paradoxical concluded that Christ God was not only God and human but, but he also exercised his divine and human attributes. The Kenotic View is such that God became a human being. This view holds the point that God the father laid down his heavenly powers and made himself available hence making himself human like us. Thus, Jesus did not cease to be the Second person in the Trinity but put aside his power to be able to serve his purpose on earth. This argument was supported by (2:5-8),explaining that even though Jesus was in the Likeness of God he did not take advantage and make himself equal with him. And as such should be our mindset that even though Jesus came on earth us a human being, we should make ourselves equal with him as his spiritual attributes is still in place. Jesus did not have an idea about what was going to happen as in when he was going to return but still kept his duties on earth. As he left his riches, thus he who once rich became poor so we could become rich, the kenotic View gives believers a logical reason for Jesus being human and God as compared to Christology. It also makes believers take Jesus humanity on a more serious level. Even with tis view there were objection made about the Kenotic view such the undermining of Christ’s divinity, how Jesus did his miraculous deeds if it’s said he did not have his divine power and Paul’s interest in metaphysical.

Importance of Discrete Mathematics in Computer Science

Importance of Discrete Mathematics in Computer Science Computer science is the study of problems, problem solving and the solutions that come out of the problem solving process, B. Miller and D. Ranum (2013). A computer scientist goal is to develop an algorithm, a step by step list of instructions in solving a problem. Algorithms are finite processes that if followed will solve the problem Discrete mathematics is concerned with structures which take on a discrete value often infinite in nature. Just as the real-number system plays a crucial role in continuous mathematics, integers are the cornerstone in discrete mathematics. Discrete mathematics provides excellent modelling tools for analysing real-world phenomena that varies in one state or another and is a vital tool used in a wide range of applications, from computers to telephone call routing and from personnel assignments to genetics, E.R. Scheinerman (2000) cited in W. J. Rapaport 2013). The difference between discrete mathematics and other disciplines is the basic foundation on proof as its modus operandi for determining truth, whereas science for example, relies on carefully analysed experience. According to J. Barwise and J. Etchemendy, (2000), a proof is any reasoned argument accepted as such by other mathematicians. Discrete mathematics is the background behind many computer operations (A. Purkiss 2014, slide 2) and is therefore essential in computer science. According to the National Council of Teachers of Mathematics (2000), discrete mathematics is an essential part of the educational curriculum (Principles and Standards for School Mathematics, p. 31). K. H Rosen (2012) cites several important reasons for studying discrete mathematics including the ability to comprehend mathematical arguments. In addition he argues discrete mathematics is the gateway to advanced courses in mathematical sciences. This essay will discuss the importance of discrete mathematics in computer science. Furthermore, it will attempt to provide an understanding of important related mathematical concepts and demonstrate with evidence based research why these concepts are essential in computer science. The essay will be divided into sections. Section one will define and discuss the importance of discrete mathematics. The second section will focus on and discuss discrete structures and relationships with objects. The set theory would be used as an example and will give a brief understanding of the concept. The third section will highlight the importance of mathematical reasoning. Finally, the essay will conclude with an overview of why discrete mathematics is essential in computer science. Discrete Mathematics According to K. H. Rosen, (2012) discrete mathematics has more than one purpose but more importantly it equips computer science students with logical and mathematical skills. Discrete mathematics is the study of mathematics that underpins computer science, with a focus on discrete structures, for example, graphs, trees and networks, K H Rosen (2012). It is a contemporary field of mathematics widely used in business and industry. Often referred to as the mathematics of computers, or the mathematics used to optimize finite systems (Core-Plus Mathematics Project 2014). It is an important part of the high school mathematics curriculum. Discreet mathematics is a branch of mathematics dealing with objects that can assume only distinct separated values (mathworld wolfram.com). Discrete mathematics is used in contrast with continuous mathematics, a branch of mathematics dealing with objects that can vary smoothly including calculus (mathworld wolfram.com). Discrete mathematics includes graph theory, theory of computation, congruences and recurrence relations to name but a few of its associated topics (mathworld wolfram.com). Discrete mathematics deals with discrete objects which are separated from each other. Examples of discrete objects include integers, and rational numbers. A discrete object has known and definable boundaries which allows the beginning and the end to be easily identified. Other examples of discrete objects include buildings, lakes, cars and people. For many objects, their boundaries can be represented and modelled as either continuous or discrete, (Discrete and Continuous Data, 2008). A major reason discrete mathematics is essential for the computer scientist, is, it allows handling of infinity or large quantity and indefiniteness and the results from formal approaches are reusable. Discrete Structures To understand discrete mathematics a student must have a firm understanding of how to work with discrete structures. These discrete structures are abstract mathematical structures used to represent discrete objects and relationships between these objects. The discrete objects include sets, relations, permutations and graphs. Many important discrete structures are built using sets which are collections of objects K H Rosen (2012). Sets As stated by Cantor (1895: 282) cited in J. L. Bell (1998) a set is a collection of definite, well- differentiated objects. K. H Rosen (2012) states discrete structures are built using sets, which are collections of objects used extensively in counting problems; relations, sets of ordered pairs that represent relationships between objects, graphs, sets of vertices and edges that connect vertices and edges that connect vertices; and finite state machines, used to model computing machines. Sets are used to group objects together and often have similar properties. For example, all employees working for the same organisation make up a set. Furthermore those employees who work in the accounts department form a set that can be obtained by taking the elements common to the first two collections. A set is an unordered collection of objects, called elements or members of the set. A set is said to contain its elements. To denote that a is an element of the set A, we write a â‚ ¬ A. For example the set O of odd positive integers less than 10 can be expressed by O = {1, 3, 5, 7, 9}. Another example is, {x |1 ≠¤ x ≠¤ 2 and x is a real number.} represents the set of real numbers between 1 and 2 and {x | x is the square of an integer and x ≠¤ 100} represents the set {0. 1, 4, 9, 16, 25, 36, 49, 64, 81, 100}, (www.cs.odu.edu). Mathematical Reasoning Logic is the science for reasoning, Copi, (1971) and a collection of rules used in carrying out logical reasoning. The foundation for logic was laid down by the British mathematician George Boole. Logic is the basis of all mathematical reasoning and of all automated reasoning. It has practical applications to the design of computing machines, to the specification of systems, to artificial intelligence, to computer programming, to programming languages and to other areas of computer science, K H Rosen, (2012 page 1). Mathematical logic, starts with developing an abstract model of the process of reasoning in mathematics, D. W. Kucker page 1. Following the development of an abstract model a study of the model to determine some of its properties is necessary. The aim of logic in computer science is to develop languages to model the situations we encounter as computer science professionals, in such a way that we can reason about them formally. Reasoning about situations means constructing arguments about them; we want to do this formally, so that the arguments are valid and can be defended rigorously, or executed on a machine. In understanding mathematics we must understand what makes a correct mathematical argument, that is, a proof. As stated by C. Rota (1997) a proof is a sequence of steps which leads to the desired conclusion Proofs are used to verify that computer programs produce the correct result, to establish the security of a system and to create artificial intelligence. Logic is interested in true or false statements and how the truth or falsehood of a statement can be determined from other statements (www.cs.odu.edu). Logic is represented by symbols to represent arbitrary statements. For example the following statements are propositions â€Å"grass is green† and â€Å"2 + 2 = 5†. The first proposition has a truth value of â€Å"true† and the second â€Å"false†. According to S. Waner and S. R Constenoble (1996) a proposition is any declarative sentence which is either true or false. Many in the computing community have expressed the view that logic is an essential topic in the field of computer science (e.g., Galton, 1992; Gibbs Tucker, 1986; Sperschneider Antoniou, 1991). There has also been concern that the introduction of logic to computer science students has been and is being neglected (e.g., Dijkstra, 1989; Gries, 1990). In their article â€Å"A review of several programs for the teaching of logic†, Goldson, Reeves and Bornat (1993) stated: There has been an explosion of interest in the use of logic in computer science in recent years. This is in part due to theoretical developments within academic computer science and in part due to the recent popularity of Formal Methods amongst software engineers. There is now a widespread and growing recognition that formal techniques are central to the subject and that a good grasp of them is essential for a practising computer scientist. (p. 373). In his paper â€Å"The central role of mathematical logic in computer science†, Myers (1990) provided an extensive list of topics that demonstrate the importance of logic to many core areas in computer science and despite the fact that many of the topics in Myers list are more advanced than would be covered in a typical undergraduate program, the full list of topics covers much of the breadth and depth of the curriculum guidelines for computer science, Tucker (1990). The model program report (IEEE, 1983) described discrete mathematics as a subject area of mathematics that is crucial to computer science and engineering. The discrete mathematics course was to be a pre or co requisite of all 13 core subject areas except Fundamentals of Computing which had no pre requisites. However in Shaw’s (1985) opinion the IEEE program was strong mathematically but disappointing due to a heavy bias toward hardware and its failure to expose basic connections between hardware and software. In more recent years a task force had been set up to deve lop computer science curricula with the creation of a document known as the Denning Report, (Denning, 1989). The report became instrumental in developing computer science curriculum. In a discussion of the vital role of mathematics in the computing curriculum, the committee stated, mathematical maturity, as commonly attained through logically rigorous mathematics courses is essential to successful mastery of several fundamental topics in computing, (Tucker, 1990, p.27). It is generally agreed that students in undergraduate computer science programs should have a strong basis in mathematics and attempts to recommend which mathematics courses should be required, the number of mathematics courses and when the courses should be taken have been the source of much controversy (Berztiss, 1987; Dijkstra, 1989; Gries, 1990; Ralston and Shaw, 1980; Saiedian 1992). A central theme in the controversy within the computer science community has been the course discrete mathematics. In 1989, the Mathematical Association of America published a report about discrete mathematics at the undergraduate level (Ralston, 1989). The report made some recommendations including offering discrete mathematics courses with greater emphasis on problem solving and symbolic reasoning (Ralston, 1989; Myers, 1990). Conclusion The paper discussed the importance of discrete mathematics in computer science and its significance as a skill for the aspiring computer scientist. In addition some examples of this were highlighted including its usefulness in modelling tools to analyse real world events. This includes its wide range of applications such as computers, telephones, and other scientific phenomena. The next section looked at discrete structures as a concept of abstract mathematical structures and the development of set theory a sub topic within discrete mathematics. The essay concluded with a literature review of evidence based research in mathematical reasoning where various views and opinions of researchers, academics and other stakeholders were discussed and explored. The review makes clear of the overwhelming significance and evidence stacked in favour for students of computer science courses embarking on discrete mathematics. Overall, it is generally clear that pursuit of a computer science course w ould most definitely need the associated attributes in logical thinking skills, problem solving skills and a thorough understanding of the concepts. In addition the review included views of an increased interest in the use of logic in computer science in recent years. Furthermore formal techniques have been acknowledged and attributed as central to the subject of discrete mathematics in recent years. References A. Purkiss 2014, Lecture 1: Course Introduction and Numerical Representation, Birkbeck University. B. Miller and D. Ranum 2013. Problem Solving with Algorithms and Data Structures: accessed on [18.01.15] Berztiss, A. (1987). A mathematically focused curriculum for computer science. Communications of the ACM, 30 (5), 356–365. Copi, I. M. (1979). Symbolic Logic (5th ed.). New York: Macmillan Core-Plus Mathematics Project 2014: Discrete Mathematics available at http://www.wmich.edu/cpmp/parentresource/discrete.html [accessed on 25.01.14] 6. D W Kucker Notes on Mathematical Logic; University of Maryland, College Park. Available at http://www.math.umd.edu/~dkueker/712.pdf Accessed on [24.01.15] Denning, P. J. (chair). (1989). Computing as a discipline. Communications of the ACM, 32 (1), 9–23. Dijkstra, E. W. (1989). On the cruelty of really teaching computing science. Communications of the ACM, 32 (12), 1398–1404. Discrete and Continuous Data, (2008). Environmental Systems Research Institute, Inc. Available at http://webhelp.esri.com/arcgisdesktop/9.2/index.cfm?TopicName=Discrete%20and%20continuous%20data [accessed on 18.01.15]. Discrete Structures (2010) available at http://www.cs.odu.edu/~toida/nerzic/content/schedule/schedule.html#day3 [accessed on 25.01.15] Edward R. Scheinerman (2000), Mathematics, A Discrete Introduction (Brooks/Cole, Pacific Grove, CA, 2000): xvii–xviii. Cited in W. J. Rapaport (2013). Discrete Structures. What is Discrete Maths? available from http://www.cse.buffalo.edu/~rapaport/191/whatisdiscmath.html-20130629 accessed on [25.01.2015] Galton, A. (1992). Logic as a Formal Method. The Computer Journal 35 (5), 431–440 Gibbs, N. E., Tucker, A. B. (1986). A model curriculum for a liberal arts degree in computer science. Communications of the ACM 29 (3), 202–210 Goldson, D., Reeves, S., Bornat, R. (1993). A review of several programs for the teaching of logic. The Computer Journal, 36 (4), 373–386. Gries, D. (1990). Calculation and discrimination: A more effective curriculum. Communications of the ACM. 34 (3). 44–55. 16. http://www.cs.odu.edu/~toida/nerzic/content/intro2discrete/intro2discrete.html : Introduction to Discrete Structures What’s and Whys IEEE Model Program Committee. (1983). The 1983 IEEE Computer Society Model Program in Computer Science and Engineering. IEEE Computer Society. Educational Activities Board J. Barwise and J. Etchemendy, Language, Proof and Logic, Seven Bridges Press, New York, 2000, ISBN 1-889119-08-3. J. L. Bell Oppositions and Paradoxes in Mathematics and Philosophy available at http://publish.uwo.ca/~jbell/Oppositions%20and%20Paradoxes%20in%20Mathematics2.pdf accessed on [25.01.2015] 20. K. H Rosen 2012 Discrete Mathematics and its Applications, 7edn, Monmouth University. Myers, Jr. J. P. (1990). The Central role of mathematical logic in computer science. SIGCSE Bulletin, 22 (1), 22–26. Ralston, A. (Ed.) (1989). Discrete Mathematics in the First Two Years. MAA Notes No. 15. The Mathematical Association of America. Ralston, A., Shaw, M. (1980). Curriculum 78 Is computer science really that unmathematical? Communications of the ACM, 23 (2), 67–70. Rota, G.-C. (1997). The phenomenology of mathematical proof. Syntheses, 111:183-196. S. Waner S. R. Costenoble (1996) Introduction to Logic. Saiedian, H. (1992). Mathematics of computing. Computer Science Education, 3 (3), 203-221. Shaw, M. (Ed.) (1985). The Carnegie-Mellon Curriculum for Undergraduate Computer Science. New York: Springer-Verlag Sperschneider, V., Antoniou, G. (1991). Logic: A foundation for computer science International Computer Science Series. Reading, MA: Addison- Wesley The National Council of Teachers of Mathematics (2000). Principles and Standards for School Mathematics. Tucker, A. B. (Ed.) (1990). Computing Curricula 1991: Report of the ACM/IEEE-CS Joint Curriculum Task Force Final Draft, December 17. ACM Order Number 201910. IEEE Computer Society Press Order Number 2220

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