Essay The Ivory Trade Ban - 2541 Words

A small herd of elephants spends the afternoon grazing on the wind swept grass of the savannah in the sweltering African sun. A few young calves playfully bounce around their mother’s legs. This peaceful vision is just a time of quiet before a bloody scene unfolds. What this small herd is blissfully unaware of is that poachers are quietly stalking them with murderous intent. This herd of elephants has a plethora of â€Å"white gold†. These poachers are after only one thing from the elephants, they are after their tusk made of ivory. By the end of the day the herd will practically be obliterated with only a small number of lucky survivors. Unfortunately, poaching elephants is not an atypical event throughout man African countries.†¦show more content†¦The US provided aid to those countries who stood to lose the most from the ban. Countries like Botswana, Kenya, and Namibia had successfully managed the elephant populations within their boundaries. On a few occasions the ban has been lifted in order to allow countries to sell, for profit, the large stocks of ivory tusks that have been accumulated from elephants who either died from natural causes, poaching, or had to be destroyed. CITES has voted to lift the ban twice. Once in 1999 which resulted in a one-time sale of 60 tons of ivory and another lift was authorized in 2002 (CITES revises ivory trade policy. and Randerson, James 2). The administration of President William J. Clinton supported the lifting the ban to allow the countries to sell remaining stocks of ivory as long as there was an agreement to use a portion of the proceeds to fund conservation and preservation programs (Clinton Statement on Proposals To Reopen Trade in Elephant Ivory and Whale Products.†). There are 37 countries or â€Å"range states† through out sub-Saharan Africa in which elephants are found (Poilecot, NGakoutou, and Taloua 9). To many indigenous people elephants are a source of bush meat, but their ‘white gold’ can prove to be a substantial reward for poachers. For example in Kenya and uncarved piece of ivory in 1969 was worthShow MoreRelated The Ivory Trade and the Slaughter of Elephants776 Words   |  4 PagesThe Ivory Trade and the Slaughter of Elephants It is hard to equate an austere piano recital with the murder of hundreds of thousands of wild animals. For that matter, it is equally as difficult to relate that horrific scene with my grandmother’s antique hairpins, but the fact of the matter is that the creamy ivory that is so cherished as a sign of wealth, culture, and tradition is really the result of the work of poachers. How can those delicate hairpins be the topic of international debateRead MoreIllegal Animal Trade Essay890 Words   |  4 Pagesspecies of animals have gone extinct (Ryder, 214). Illegal trade generates billions of dollars and is therefore highly popular. There have been many regulations placed upon this trading. Some have been successful and others have not. Governments across the world have placed regulations on this illegal trade and treatment of animals, but it is still an issue. To what extent have governments been successful in stemming illegal animal trade? People smuggle animals for many different reasons. Some believeRead MoreThe Ivory Trade Is An Important Issue1584 Words   |  7 PagesIn the world today, the global ivory trade is one of the most profitable and complex areas of poaching. The range and impact of the ivory trade is vast and devastating as it encompasses many countries in Africa, Asia, and even the United States. Thousands of elephants are being threatened and killed everyday for their tusks to be sold and be used for ornaments and carvings. While the issue may seem easy to understand, beneath the surface is a crisis that extends to many spectrums such as culturalRead MoreSummary : The Scourge Of The Ivory Trade 1152 Words   |  5 PagesKilling for Teeth? Doesn’t Seem Right In, â€Å"The Scourge of the Ivory Trade† the editorial board discusses the need to put a ban on the importing and exporting of illegal ivory into China. Over the last decade, the demand for ivory has skyrocketed in China. The board explains that there have been some strides made in the right direction, but not nearly enough has been done. The population of elephants in Tanzania alone has lost nearly ninety percent of their population (The Editorial Board). TheRead MoreA Good Deed Of The Elephants1639 Words   |  7 Pagesholding a large stockpile of ivory tusks from decades of collecting (DocuMatForEdu1, 2016). All the tusks range in size, so the tusks were taken from elephants of all sizes, from youngling to mature adults. These diverse collection of tusks are kept by the government because it sees value in it. The government notices the booming ivory trade industry, and they believe selling the stockpile one day will bring profit to the nation. Then, the profit brought from the trade will be used for conservationRead MoreInternational Union For Conservation Of Nature1488 Words   |  6 Pagesanimals by protecting them better and to be able to file lawsuits to anyone who commits in destroying animal wildlife. The House of Representatives of Pennsylvania has issued a new bill in the beginning year of 2017 establishing the end of elephant ivory and rhinoceros horns trading sales. The House Bill 248 is the best policy because it will put an end to poaching elephants and rhinoceros as well as selling and taking possessions of both items saving millions of dollars and giving these beautifulRead MoreThe Ivory Trade And Its Effect On The Trade1845 Words   |  8 Pagesthe world. The ivory trade is a practice that has been in place for centuries. In the last one to two hundred years, the negative impacts of the trade have begun to surface. The elephant populations, specifically in Africa, are rapidly declining with the illegal trade taking place today. The ban on the ivory trade was put into place in order to save the elephant populations and reduce the harmful environmental impacts. The use of international law in the creation of the ban on the trade and the currentRead MoreElephants : Sub Sahara Africa1719 Words   |  7 Pageshuge tusks that enables them to strip bark from trees, and to dig for food. The elephants also use the tusks to fight one another but, the need of ivory has contributed to a lot more dangerous stunts. Ivory has become valuable to people in Africa and all over the world that it has led to a large number of deaths of elephants for the tusks. Ivory trade in the past twenty years has been made illegal but, however, it has not been fully eradicated which has led to the elephant population to be endangeredRead MoreThe Heart Of Darkness By Joseph Conrad983 Words   |  4 Pagesimmoral humans can be when pursuing greed and power. The Heart of Darkness by Joseph Conrad gives us a good understanding of the real li fe issues that affected the Congo Independent State in the 1890s which included European imperialism, free market ivory trade, and many European atrocities against the African natives. European imperialism was forced on the Congo Independent State by King Leopold II. â€Å"In aspiring to become a modern-day pharaoh, King Leopold began his African venture in September 1876†Read MoreThe World s Largest African Elephant1125 Words   |  5 Pagesto the ground. The carcass of 45-year-old elephant with its face mutilated and great tusks hacked off was left for vultures and scavengers. Poachers had killed Satao with poisoned arrows for the ivory that weighed over 100 pounds. According to the data provided by Landmark Analysis, poachers seeking ivory had killed more than 100,000 African elephants in just three years. One of the largest mass elephant slaughter in decades took place in Cameroon, in 2012 where poachers using Ak47s and grenades had

Before The Birth Of Science, The Origin Of Fire Could Only

Before the birth of science, the origin of fire could only be speculated by humanity. The Greeks said Prometheus stole fire from the gods and gave it to humans. They also considered fire to be one of the five basic elements of the universe. The Chinese say Hui Lu kept one hundred fire birds in a gourd that had the power to cause forest fires5. The Native Americans explain fire by stating fire was hidden from mankind and that an animal—coyote, woodpecker, or wolf—would steal the fire from the guarded Fire Mountain5. A later theory in the seventeenth century stated that objects containing phlogiston had the ability to catch fire, thus explaining combustion and rusting in archaic times3. However later observations disproved the theory. In†¦show more content†¦From one stable compound comes multiple products caused by the rearrangement of the reactant. If one were to do the calculations for the combustion reaction, the units would be in joules and negative, indicat ing it is an exothermic reaction. Such calculations are vital to maximize output and feed consumption. Today’s demand for electricity is voracious, consuming 3913 billion kilowatt-hours in the United States alone6. According to the Wall Street Journal, coal is currently one of the most used fuel source to produce the United States’ energy along with natural gas, petroleum, renewable energy, and nuclear power1. For a long time, coal has been the best heat source since it contains more heat per gram and potential energy compared to wood’s meager output4. To use coal to produce electricity, the coal is heated and cooled with water. The water vapor is used to turn a turbine connected to a generator, and is later condensed back into liquid water and returned to a body of water or recycled4. The chemical formula of coal is C135H96O9NS from carbonized plant biomass but varies from different coal qualities, ranging from anthracite to peat1. What differs between each quality of coal is the amount of carbon, oxygen, and impurities such as mercury and sulfur. These impuritie s affect the amount of pollution that gets expelled into the atmosphere such as sulfur dioxide and poisonous mercury gas4. As a result, these pollutants cause respiratory problems and acidify waterShow MoreRelatedConflicts Between Science and Religion1662 Words   |  7 Pagesï » ¿Introduction - In science, evolution is one of the basic templates for understanding the biology of an organism or ecological unit. Essentially, it is the change in inherited traits of a population through a process called natural selection in which only the strongest traits are appropriately adapted to the environment in question. Those traits from parents who are healthier and live longer are then passed down to future generations where the traits are amplified if the organism thrives. EvolutionRead MoreThe Plan B Pill1608 Words   |  6 Pagesintercourse, some methods can be used within a short time after unprotected intercourse or failed use of birth control, which are usually referred to as emergen cy contraceptive. Within the last 30 years, a number of approaches, which seem safe and efficacious, have been developed as this method, including the popular plan B pill. In 1999 the FDA approved the Plan B pill, which was the first progestin-only dedicated emergency contraceptive product. The plan B pill was developed by Teva Pharmaceutical IndustriesRead MoreHistory of Science and Technology1800 Words   |  8 PagesScience and Technology has been around from the beginning of time. It evolved from the everyday efforts of people trying to improve their way of life. Throughout history, humankind has developed and utilized tools, machines, and techniques without understanding how or why they worked or comprehending their physical or chemical composition. Before we go any further a definition has to be given for both Science and Technology because they are both different in their own right even though the two areRead More Greek Fire, the Most Powerful Weapon of Byzantine Army Essay4 481 Words   |  18 Pages War is the father of all things.1 Volkman begins his book, Science Goes to War, with this quote from Heraclitus, the Greek philosopher. Volkman uses the quote to suggest that many, if not all, scientific advancements owe their birth to the desire for or the fear of war. Fire is undoubtedly a part of this advancement as Bert Hall points out, Fire is one of the primordial forces of nature, and incendiary weapons have had a place in armies toolkits for almost as long as civilized states have madeRead MoreVampires Are The Reason Behind The Vampire1749 Words   |  7 Pagesmany books and movies, vampires have been glamorized as creatures the world adores today. In short, although vampires have become a staple in the entertainment of the developed world, many people still argue that this blood-sucking, undead being is only a figment of the imagination, while fanatics continue to argue its existence. Vampires are said to be fallen angels that were cast out of heaven. According to Dictionary.com, vampires are defined as â€Å"a corpse, animated by an undeparted soul or demonRead MorePrometheus : Alien Religion.1902 Words   |  8 PagesSomtochukwu BOC-Ifeobu Dr. Detore-Nakamura HU 145 (Themes in Humanities) 2 December 2014 Prometheus: Alien Religion Prometheus is a 2012 science-fiction movie directed by Ridley Scott. In this movie, a group of humans leave earth in the year 2093 on a ship called Prometheus for a distant planet in search of the creators of humanity or engineers. While watching this movie, one can notice many Judeo-Christian themes and references to Christianity’s Jesus Christ. Based on these references, the movieRead MoreAncient Egypt1704 Words   |  7 PagesAncient Egypt The giant pyramids, temples, and tombs of ancient Egypt tell an exciting story about a nation that rose to power more than 5,000 years ago. This mighty civilization crumbled before conquering armies after 2,500 years of triumph and glory. The dry air and drifting desert sands have preserved many records of ancient Egypt until modern times. The ancient Egyptians lived colorful, active, and eventful lives. Many were creative artists, skilled craftsmen, and adventurous explorersRead MoreArchimedes Background/Upbringing - Paper1497 Words   |  6 Pagesmirrors that would burn the Roman ships. The exact years of his birth and death are uncertain, but Greek historian John Tzetes believes he lived to be 75 years old (â€Å"Archimedes†, n.d). Archimedes father was named Phidias who was an astronomer. His mother’s name is unknown, but there is belief that Archimedes is related to the Ruler of Syracuse King Hiero II. There are currently not many documents of Archimedes upbringing. In fact there is only one record of his life that was written by his friend HeracleidesRead MoreThe Exorcist Defines the Horror Genre Essay1482 Words   |  6 Pagesidentified by its heavy emphasis on evoking emotion; specifically those emotions that make the audience feel uncomfortable (panic, shock, disgust, fear, etc). In fact, emotion plays such an important role in defining this genre, it joins a lis t of only two genres that diverge their intended effect though the name—Horror and Romance. Heimerdinger says that â€Å"The goal of the genre is to get in touch with primal fears and bring people’s nightmares to life† (Heimerdinger). Steffen Hantke is the authorRead MoreEssay about Ancient Egypt1687 Words   |  7 Pages Ancient Egypt nbsp;nbsp;nbsp;nbsp;nbsp;The giant pyramids, temples, and tombs of ancient Egypt tell an exciting story about a nation that rose to power more than 5,000 years ago. This mighty civilization crumbled before conquering armies after 2,500 years of triumph and glory. The dry air and drifting desert sands have preserved many records of ancient Egypt until modern times. nbsp;nbsp;nbsp;nbsp;nbsp;The ancient Egyptians lived colorful, active, and eventful lives. Many were creative

First meeting Issues Free Essays

In the first meeting of the Land Committee held on 22nd December, 2004 it was decided to hold public hearings with recognized political parties, civil society organizations and peoples? unions working on land issues of the poor to understand the various issues on land reforms. The Committee held public hearings in Hydrated, Wrangle, Vigilant and Atrophic. The visits to the districts and public meetings were followed by field visits to districts and villages to get a firsthand knowledge of the land issues affecting the poor. We will write a custom essay sample on First meeting Issues or any similar topic only for you Order Now In an overwhelming response, political parties and civil society organizations attended all the public hearings and cutting across party lines, have demanded that land issues affecting the poor required immediate attention by the Government. Commissioning of Studies In order to understand the land issues in greater detail and also the relevance and use of the existing Revenue Acts, the committee has commissioned studies on various aspects of land issues by specialists and experts. Studies have been conducted on Board Standing Orders and Revenue Acts, Tribal land issues, issues of Tenancy, the phenomenon of absentee landlord’s and that of plain paper transactions (Sad bambina transactions), functioning of the legal system and state of the endowment lands (Terms of References of the studies and consultants/consulting organizations conducting the study enclosed). Recommendations immediately operational in nature While commissioning the studies the Land Committee was very clear that recommendations evolving from the studies would not be theoretical in nature and focus shall be on operational issues. The Committee has tried its best to cover the important and pressing land issues. The recommendations of the committee while not exhaustive nevertheless cover substantial ground. Page 3 of 101 Land still the single most emotive issue in rural areas It has been the Committee?s experience that the issue of land continues to be the single most emotive issue in the rural areas. How to cite First meeting Issues, Papers

Miss Johnson in Going to the Moon free essay sample

Going to the Moon Many authors use symbols as a device in their texts. In â€Å"Going to the Moon†, by Nina Ricci, symbolism is used to illuminate the themes and provide a deeper meaning to the short story. The teacher in the short story, Miss Johnson is the most important symbol. Miss Johnson is a necessary symbol because she represents important themes throughout, including the connection between the narrator and his peers, hope for the narrator and acceptance of the narrator. Miss Johnson represents the single connection that the narrator and his peers share, providing a sense of security for the boy to avoid humiliation and teasing. The narrator and his classmates both share a deep love for Miss Johnson: â€Å"I felt protected in that common love, in the importance I gained in sharing it, as if I’d been included in a game that could have no losers, no chance for ridicule or shame† (Page 213). We will write a custom essay sample on Miss Johnson in Going to the Moon or any similar topic specifically for you Do Not WasteYour Time HIRE WRITER Only 13.90 / page Miss Johnson is a very important symbol in the play because the connection that she made possible was very important to the narrator as a sense of protection from his peers bantering and a sense of being equal and similar to his classmates. Just as Miss Johnson represents the connection between the narrator and his peers, she also represents hope for the narrator’s future. Whenever the narrator is in the presence of Miss Johnson, he feels optimistic towards and confident about his life and how it will unfold. His thoughts when he goes to school and sees Miss Johnson entail: â€Å"†¦I felt the small bright hope that my life could be different, that the things marked me out could be erased, a hope made urgent, desperate, by the love that I felt for our teacher Miss Johnson† (Page 212). Miss Johnson also represents hope for the narrator because she is different form all of her colleagues, however, she is still accepted and respected by her students: â€Å"Miss Johnson was one of the few lay teachers at Assumption, and she stood out form the stiff formality of the priests and nuns like a burst of colour in a grey landscape, coming to school in lipstick and high heels†¦ in blouses of shimmering silk,†¦ and we and we were all in love with her, proudly, self-importantly, all hoped to be chosen by her to wipe the blackboards or fetch chalk from the storeroom† (Pages 212-213). Miss Johnson is the most important symbol in the play because the hope that the narrator feels for his life to be better is planted by the existence of Miss Johnson, and his loving thoughts towards her. Miss Johnson not only represents hope, but she also represents acceptance of the narrator. Miss Johnson is one of the few, if not the only one who accepts the narrator in this short story. She shows her acceptance of the boy when he stays inside during recess with her to help her with a bulletin board in the classroom: â€Å"†¦she began to hum some song softly to herself as if she had forgotten that I was standing beneath her; and it made me feel oddly relieved to be taken for granted like that, to have been drawn unthinkingly into the small private sphere of Miss Johnson’s aloneness as if there were nothing strange or remarkable about me† (Page 213). The acceptance towards the narrator that Miss Johnson represents is another reason why Miss Johnson is the most important symbol in the short story. Miss Johnson is not only a teacher in the story, she is also a significant symbol which represents important themes in the short story including: acceptance for the narrator; hope for the narrator, and the bridge that connects the narrator to the children in his class. Without Miss Johnson none of these themes would be apparent, and the boy would have little hope for the future. Miss Johnson is a crucial symbol in this short story.

The Major Conflict In The Novel, Cry The Beloved Country, Is An Inner

The major conflict in the novel, Cry the Beloved Country, is an inner uncertainty within the characters. The author, Alan Paton, shows this inner conflict from two perspectives; the Europeans and the Native South Africans. These two groups also have inconsistencies in their conscious to resolve. The black Natives are struggling between tradition and the new world. The Natives are forfeiting their old values as they progress towards the mode of the big city life. The Europeans are also confused. Many Europeans want to help the Natives, but are faced with following old tradition. Conventionally, these two groups should live independently. The changing of customs and values created apprehension and fear for both groups of people. Steven Kumalo, a Native priest, faced inner conflicts throughout the book. Kumalo had dreams of restoring the tribe and reuniting his family. He received a letter telling him his sister was ill in Johannesburg. Steven overcomes his fears of the big city and attempts to reunite his broken family. Steven hoped to find his sister Gertrude, brother John, and son Absalom. Each of these characters rejected their old values. His brother, John, was a corrupt politician. Kumalo's sister, Gertrude, was a prostitute. Absalom, Stephen's son, killed Arthur Jarvis. Kumalo struggled with feelings about his family members. He continued to encounter the clash of two different worlds affecting their lives. The Europeans were caught between tradition and the modernistic ways. The Europeans had been taught they were a superior race. Many Europeans doubted their traditional views and lifestyles. During the Native's bus boycott, a few Europeans voluntarily drove the Natives so they did not have to walk. The old routine customs were questioned, and challenged. In this case, the rules were ignored. Customs were also ignored during Absalom's trial. Absalom Kumalo, Stephen's son, was found guilty of murdering Arthur Jarvis. Absalom's white friend broke the color line while leaving the courtroom. Carmichael ran to help Stephen who was about to collapse from devastating grief for his son. Helping a friend, rather than obeying tradition was Carmichael's response to this inner conflict. Jarvis and Kumalo began interacting with each other when they returned to Natal. Mr. Jarvis's grandson visited Stephen's home a few times before returning to Johannesburg. Kumalo taught the young boy the Native Zulu language. The boy was a respectful and attentive student. Mr. Jarvis's grandson challenged the old ways and accepted his teacher. It was much easier for the younger generations to accept the challenges of change. The younger generations had different views about racial issues than their parents. Mr. Kumalo hoped the younger generations would prosper and live peacefully. James Jarvis and Stephen Kumalo returned to their homes in Natal. A deadly drought had devastated the land. Mr. Kumalo turned to tradition for an end to the drought. He visited the tribal chief for help. The chief told Kumalo there is nothing to be done and they will pray for rain. Stephen Kumalo and many others viewed the chief as just a figurehead. Kumalo's trip to Johannesburg taught him to accept new ways and ideas. Stephen Kumalo questioned traditional solutions to the current problems in his land. James Jarvis returned to help the Native tribal community. He hired a new teacher for the school. The teacher informed the Natives of new farming methods. The new knowledge helped the natives through the drought. Mr. Jarvis also gave the Natives milk for the young children until they could get enough of their own. He also offered to build Stephen a new church. Jarvis ignored belief and custom to help people in need, regardless of their skin color. Alan Paton's novel presents the personal conflict of Jarvis and Kumalo. Through their lives, the larger conflict between the races in South Africa and for all humanity is presented by this wonderful author.

Circular Motion Essays

Circular Motion Essays Circular Motion Paper Circular Motion Paper Circular motion is the motion that links velocity, mass, and radius of the string of an object. If any one of the factors is changed, the motion of the object gets affected or the velocity/acceleration gets affected. All objects going through circular motion experience a force called the centripetal force. Centripetal force is the force that acts from the center of the circular path and makes the object move in the curve instead of flying out. In other words, centripetal force is the force that originates from the center and is directed inwards. Also, one important factor in this lab is that the circular motion will be horizontal. In this experiment, the factor that will be changed is the radius of the string. This will bring in a direct change in the motion of the rubber stopper attached to the string. The string will pass through a plastic tube, which will be holding gear and the time for 10 rotations of the rubber stopper will be timed by a stop watch. The velocity will be calculated by using the universally known formula: v = (2r) / t , where v is the velocity, r is the radius of the string and t is the time for one rotation. The main purpose of this experiment is to find out one factor that affects the motion of a rubber stopper in circular motion. In this lab, this factor is the change in radius of the string that is attached to the rubber stopper. In this experiment, the factor that will be changed is the radius of the string. As the radius of the string decreases, the speed of the revolving rubber stopper increases. This would happen because as the radius decreases, the rubber stopper takes less time to circle around with the constant centripetal force on it. In other words as the radius decreases, the size of the circle decreases, hence it takes less time to cover a smaller circle, with the same force acting on the rubber stopper. In other words, the radius of the string is inversely proportional to the velocity of the stopper. Overall, the experiment was carried out with minimum errors and followed as the procedure. There were eight data points with three trials each. The experiment was related to one factor that affected the motion of the rubber stopper in circular motion. In this experiment, that factor was the length of the string (radius). As stated in the hypothesis, the radius was decreased which would increase the velocity of the stopper. But as it can be seen from the data table and graph that as the radius decreased the velocity also decreased. Hence, the radius of the string is directly proportional to the velocity of the stopper. This proves my hypothesis wrong which stated that as the radius decreases, the velocity increases. In my experiment, the radius was decreased which decreased the time elapsed but decreased the velocity as well. This would have happened because as the radius decreased, the stopper actually has to move faster in order to cover the larger circle in the same amount of time. The stopper actually covers much more area of the circle when the radius is larger without taking more time. This theory is exactly opposite as stated in my hypothesis. As it can be seen from my graph and the data table that there were some errors in my experiment. The percent error that was calculated to be 13. 5 % assures the fact that there were flaws in my experiment. One big error was that when the stopper was revolving, the hand often touched the string of the stopper. This often altered the centripetal force acting on the string, hence changing the values of my data. Another error was that not all the time the radius mark (the mark on the string with the marker) used to be exactly under the plastic pipe. Because of this, the values of the radius were altered hence changing the velocity factor in my experiment. The errors/flaws stated above can be prevented by a number of steps. Always during the experiment, the only part the hand should touch is the plastic tube only. Even if the hand touches any other part of the apparatus, the experiment should be stopped carefully and the trial should be re-done. Also, instead of using a marker on the string, he string should be tapped or tagged at the point needed. The tag should be greater than the radius of the hole of the plastic tube so that the tag does not pass through the hole, hence it will not alter the value of the desired radius.

International Management Accounting Case Study Example | Topics and Well Written Essays - 500 words

International Management Accounting - Case Study Example By using this technique, Toyota sets goals for cost reduction, and then tries to achieve these new targets through design changes that will accomplish the cost reduction goal. Toyota goes through a vigorous testing phase to judge the costs of the new design in comparison with the old one, in order to guarantee a cost reduction after implementation of the new technique. This is the main idea that Toyota uses to achieve their company wide goals. Toyota Co made changes to existing automobiles and not the design of new ones.There are several steps in the sequence of price, production, and cost decisions.Toyota first decides what the new retail price of the automobile is going to be by taking the old price and adding the value of any new functions.The sales division comes up with the suggested production volume, by taking past numbers and indexing them to market trends and the state of competitors.After all these figures have been set, the focus switches to cost planning.This cost plan is based on the product plan and the targets for retail price and production volume.Toyota establishes a profit target that is subtracted to determine their target cost. These cost planning decisions are made three years before they release the model. When Toyota estimates the approximate costs of a

SP Essay Example | Topics and Well Written Essays - 250 words

SP - Essay Example I love most the way research gives researchers the opportunity to express emotions and opinions in words that touch, inspire, and influence other people. It is my hope that as a researcher, I shall instill knowledge and motivate other upcoming researchers. I am convinced that I will also learn in depth the concepts of Educational Statistics, Data Analysis, Qualitative Research, and Organizational Development. I shall use the knowledge I acquire here to increase student learning and achievements as measured on standardized scores. I always wanted to do something with my life that would ensure that I am giving back to the society. This was a motivation I got from my mother at a tender age. I therefore, intent to use the concepts I learn to inspire other people. I have always looked forward to expanding my theoretical and practical knowledge. I am convinced that my study in your well-regarded institution with such a long-term record of academic excellence backed by expert faculty and excellent research services will be a meaningful and rewarding experience. I look forward to an opportunity to study in your highly esteemed institution. With my commitment, persistence, and patience to succeed, I believe I shall see my dreams come

Deaf readings and Questionss 2 Coursework Example | Topics and Well Written Essays - 250 words

Deaf readings and Questionss 2 - Coursework Example The fact factors like gender and language also further disintegrates the students, both the disabled and the abled, should be something that can be dealt with. Parents should expose their children to different languages at an early age to avoid inconveniences. These are both the spoken and the written language (24). This would help avoid discrimination. Mertens 1990, after a thorough research on academic performance for both the students with hearing problems and the hearing students, came up with a surprising report. The performance of the hearing students was way higher than that of the non-hearing students. This may raise critics against the combined mode of learning which is putting them all in a common institution. To avoid this, i advocate that although they are to learn in the same environment, there has to be some extra or rather special classes of either of the hearing or the hard of hearing students so as to put them on almost the same

Drugs in the Treatment of Gastrointestinal Disease

Drugs in the Treatment of Gastrointestinal Disease Introduction Many of the drug groups discussed elsewhere in this book have important applications in the treatment of diseases of the gastrointestinal tract and other organs. Other groups are used almost exclusively for their effects on the gut; these are discussed in the following text according to their therapeutic uses. Drugs Used in Acid-Peptic Diseases Acid-peptic diseases include gastroesophageal reflux, peptic ulcer (gastric and duodenal), and stress-related mucosal injury. In all these conditions, mucosal erosions or ulceration arise when the caustic effects of aggressive factors (acid, pepsin, bile) overwhelm the defensive factors of the gastrointestinal mucosa (mucus and bicarbonate secretion, prostaglandins, blood flow, and the processes of restitution and regeneration after cellular injury). Over 90% of peptic ulcers are caused by infection with the bacterium Helicobacter pylori or by use of nonsteroidal anti-inflammatory drugs (NSAIDs). Drugs used in the treatment of acid-peptic disorders may be divided into two classes: agents that reduce intragastric acidity and agents that promote mucosal defense. Agents that Reduce Intragastric Acidity Physiology of Acid Secretion The parietal cell contains receptors for gastrin (CCK-B), histamine (H2), and acetylcholine (muscarinic, M3) (Figure 62-1). When acetylcholine (from vagal postganglionic nerves) or gastrin (released from antral G cells into the blood) bind to the parietal cell receptors, they cause an increase in cytosolic calcium, which in turn stimulates protein kinases that stimulate acid secretion from a H+,K+ ATPase (the proton pump) on the canalicular surface. In close proximity to the parietal cells are gut endocrine cells called enterochromaffin-like (ECL) cells. ECL cells also have receptors for gastrin and acetylcholine, which stimulate histamine release. Histamine binds to the H2 receptor on the parietal cell, resulting in activation of adenylyl cyclase, which increases intracellular cyclic adenosine monophosphate (cAMP) and activates protein kinases that stimulate acid secretion by the H+,K+ ATPase. In humans, it is believed that the major effect of gastrin upon acid secretion is mediated indirectly through the release of histamine from ECL cells rather than through direct parietal cell stimulation. In contrast, acetylcholine provides potent direct parietal cell stimulation. Antacids Antacids have been used for centuries in the treatment of patients with dyspepsia and acid-peptic disorders. They were the mainstay of treatment for acid-peptic disorders until the advent of H2-receptor antagonists and proton pump inhibitors. They continue to be used commonly by patients as nonprescription remedies for the treatment of intermittent heartburn and dyspepsia. Antacids are weak bases that react with gastric hydrochloric acid to form a salt and water. Their principal mechanism of action is reduction of intragastric acidity. After a meal, approximately 45 mEq/h of hydrochloric acid is secreted. A single dose of 156 mEq of antacid given 1 hour after a meal effectively neutralizes gastric acid for up to 2 hours. However, the acid-neutralization capacity among different proprietary formulations of antacids is highly variable, depending on their rate of dissolution (tablet versus liquid), water solubility, rate of reaction with acid, and rate of gastric emptying. Sodium bicarbonate (eg, baking soda, Alka Seltzer) reacts rapidly with hydrochloric acid (HCL) to produce carbon dioxide and sodium chloride. Formation of carbon dioxide results in gastric distention and belching. Unreacted alkali is readily absorbed, potentially causing metabolic alkalosis when given in high doses or to patients with renal insufficiency. Sodium chloride absorption may exacerbate fluid retention in patients with heart failure, hypertension, and renal insufficiency. Calcium carbonate (eg, Tums, Os-Cal) is less soluble and reacts more slowly than sodium bicarbonate with HCl to form carbon dioxide and calcium chloride (CaCl2). Like sodium bicarbonate, calcium carbonate may cause belching or metabolic alkalosis. Calcium carbonate is used for a number of other indications apart from its antacid properties (see Chapter 42). Excessive doses of either sodium bicarbonate or calcium carbonate with calcium-containing dairy products can lead to hypercalcemia, renal insufficiency , and metabolic alkalosis (milk-alkali syndrome). Formulations containing magnesium hydroxide or aluminum hydroxide react slowly with HCl to form magnesium chloride or aluminum chloride and water. Because no gas is generated, belching does not occur. Metabolic alkalosis is also uncommon because of the efficiency of the neutralization reaction. Because unabsorbed magnesium salts may cause an osmotic diarrhea and aluminum salts may cause constipation, these agents are commonly administered together in proprietary formulations (eg, Gelusil, Maalox, Mylanta) to minimize the impact on bowel function. Both magnesium and aluminum are absorbed and excreted by the kidneys. Hence, patients with renal insufficiency should not take these agents long-term. All antacids may affect the absorption of other medications by binding the drug (reducing its absorption) or by increasing intragastric pH so that the drugs dissolution or solubility (especially weakly basic or acidic drugs) is altered. Therefore, antacids should not be given within 2 hours of doses of tetracyclines, fluoroquinolones, itraconazole, and iron. H2-Receptor Antagonists From their introduction in the 1970s until the early 1990s, H2-receptor antagonists (commonly referred to as H2 blockers) were the most commonly prescribed drugs in the world (see Clinical Uses). With the recognition of the role of H pylori in ulcer disease (which may be treated with appropriate antibacterial therapy) and the advent of proton pump inhibitors, the use of prescription H2 blockers has declined markedly. Chemistry Pharmacokinetics Four H2 antagonists are in clinical use: cimetidine, ranitidine, famotidine, and nizatidine. All four agents are rapidly absorbed from the intestine. Cimetidine, ranitidine, and famotidine undergo first-pass hepatic metabolism resulting in a bioavailability of approximately 50%. Nizatidine has little first-pass metabolism. The serum half-lives of the four agents range from 1.1 to 4 hours; however, duration of action depends on the dose given (Table 62-1). H2 antagonists are cleared by a combination of hepatic metabolism, glomerular filtration, and renal tubular secretion. Dose reduction is required in patients with moderate to severe renal (and possibly severe hepatic) insufficiency. In the elderly, there is a decline of up to 50% in drug clearance as well as a significant reduction in volume of distribution. BID, twice daily; HS, bedtime. Clinical Uses H2-receptor antagonists continue to be prescribed but proton pump inhibitors (see below) are steadily replacing H2 antagonists for most clinical indications. However, the over-the-counter preparations are heavily used by the public. Gastroesophageal Reflux Disease (GERD) Patients with infrequent heartburn or dyspepsia (fewer than 3 times per week) may take either antacids or intermittent H2 antagonists. Because antacids provide rapid acid neutralization, they afford faster symptom relief than H2 antagonists. However, the effect of antacids is short-lived (1-2 hours) compared with H2 antagonists (6-10 hours). H2 antagonists may be taken prophylactically before meals in an effort to reduce the likelihood of heartburn. Frequent heartburn is better treated with twice-daily H2 antagonists (Table 62-1) or proton pump inhibitors. In patients with erosive esophagitis (approximately 50% of patients with GERD), H2 antagonists afford healing in less than 50% of patients; hence proton pump inhibitors are preferred because of their superior acid inhibition. Peptic Ulcer Disease Proton pump inhibitors have largely replaced H2 antagonists in the treatment of acute peptic ulcer disease. Nevertheless, H2 antagonists are still sometimes used. Nocturnal acid suppression by H2 antagonists affords effective ulcer healing in most patients with uncomplicated gastric and duodenal ulcers. Hence, all the agents may be administered once daily at bedtime, resulting in ulcer healing rates of more than 80-90% after 6-8 weeks of therapy. For patients with ulcers caused by aspirin or other NSAIDs, the NSAID should be discontinued. If the NSAID must be continued for clinical reasons despite active ulceration, a proton pump inhibitor should be given instead of an H2 antagonist to more reliably promote ulcer healing. For patients with acute peptic ulcers caused by H pylori, H2 antagonists no longer play a significant therapeutic role. H pylori should be treated with a 10- to 14-day course of therapy including a proton pump inhibitor and two antibiotics (see below). This regimen achieves ulcer healing and eradication of the infection in more than 90% of patients. For the minority of patients in whom H pylori cannot be successfully eradicated, H2 antagonists may be given daily at bedtime in half of the usual ulcer therapeutic dose to prevent ulcer recurrence (eg, ranitidine, 150 mg; famotidine, 20 mg). Nonulcer Dyspepsia H2 antagonists are commonly used as over-the-counter agents and prescription agents for treatment of intermittent dyspepsia not caused by peptic ulcer. However, benefit compared with placebo has never been convincingly demonstrated. Prevention of Bleeding from Stress-Related Gastritis Clinically important bleeding from upper gastrointestinal erosions or ulcers occurs in 1-5% of critically ill patients as a result of impaired mucosal defense mechanisms caused by poor perfusion. Although most critically ill patients have normal or decreased acid secretion, numerous studies have shown that agents that increase intragastric pH (H2 antagonists or proton pump inhibitors) reduce the incidence of clinically significant bleeding. However, the optimal agent is uncertain at this time. For patients without a nasoenteric tube or with significant ileus, intravenous H2 antagonists are preferable over intravenous proton pump inhibitors because of their proven efficacy and lower cost. Continuous infusions of H2 antagonists are generally preferred to bolus infusions because they achieve more consistent, sustained elevation of intragastric pH. Adverse Effects H2 antagonists are extremely safe drugs. Adverse effects occur in less than 3% of patients and include diarrhea, headache, fatigue, myalgias, and constipation. Some studies suggest that intravenous H2 antagonists (or proton pump inhibitors) may increase the risk of nosocomial pneumonia in critically ill patients. Mental status changes (confusion, hallucinations, agitation) may occur with administration of intravenous H2 antagonists, especially in patients in the intensive care unit who are elderly or who have renal or hepatic dysfunction. These events may be more common with cimetidine. Mental status changes rarely occur in ambulatory patients. Cimetidine inhibits binding of dihydrotestosterone to androgen receptors, inhibits metabolism of estradiol, and increases serum prolactin levels. When used long-term or in high doses, it may cause gynecomastia or impotence in men and galactorrhea in women. These effects are specific to cimetidine and do not occur with the other H2 antagonists. Although there are no known harmful effects on the fetus, H2 antagonists cross the placenta. Therefore, they should not be administered to pregnant women unless absolutely necessary. The H2 antagonists are secreted into breast milk and may therefore affect nursing infants. H2 antagonists may rarely cause blood dyscrasias. Blockade of cardiac H2 receptors may cause bradycardia, but this is rarely of clinical significance. Rapid intravenous infusion may cause bradycardia and hypotension through blockade of cardiac H2 receptors; therefore, intravenous injections should be given over 30 minutes. H2 antagonists rarely cause reversible abnormalities in liver chemistry. Drug Interactions Cimetidine interferes with several important hepatic cytochrome P450 drug metabolism pathways, including those catalyzed by CYP1A2, CYP2C9, CYP2D6, and CYP3A4 (see Chapter 4). Hence, the half-lives of drugs metabolized by these pathways may be prolonged. Ranitidine binds 4-10 times less avidly than cimetidine to cytochrome P450. Negligible interaction occurs with nizatidine and famotidine. H2 antagonists compete with creatinine and certain drugs (eg, procainamide) for renal tubular secretion. All of these agents except famotidine inhibit gastric first-pass metabolism of ethanol, especially in women. Although the importance of this is debated, increased bioavailability of ethanol could lead to increased blood ethanol levels. Proton Pump Inhibitors Since their introduction in the late 1980s, these efficacious acid inhibitory agents have assumed the major role for the treatment of acid-peptic disorders. Proton pump inhibitors (PPIs) are now among the most widely prescribed drugs worldwide due to their outstanding efficacy and safety. Chemistry Pharmacokinetics Five proton pump inhibitors are available for clinical use: omeprazole, lansoprazole, rabeprazole, pantoprazole, and esomeprazole. All are substituted benzimidazoles that resemble H2 antagonists in structure (Figure 62-3) but have a completely different mechanism of action. Omeprazole is a racemic mixture of R- and S-isomers. Esomeprazole is the S-isomer of omeprazole. All are available in oral formulations. Esomeprazole and pantoprazole are also available in intravenous formulations . Proton pump inhibitors are administered as inactive prodrugs. To protect the acid-labile prodrug from rapid destruction within the gastric lumen, oral products are formulated for delayed release as acid-resistant, enteric-coated capsules or tablets. After passing through the stomach into the alkaline intestinal lumen, the enteric coatings dissolve and the prodrug is absorbed. For children or patients with dysphagia or enteral feeding tubes, capsules may be opened and the microgranules mixed with apple or orange juice or mixed with soft foods (eg, applesauce). Lansoprazole is also available as a tablet formulation that disintegrates in the mouth, or it may be mixed with water and administered via oral syringe or enteral tube. Omeprazole is also available as a powder formulation (capsule or packet) that contains sodium bicarbonate (1100-1680 mg NaHCO3 ; 304-460 mg of sodium) to protect the naked (non-enteric-coated) drug from acid degradation. When administered on an empty stomach by m outh or enteral tube, this immediate-release suspension results in rapid omeprazole absorption (Tmax The proton pump inhibitors are lipophilic weak bases (pKa 4-5) and after intestinal absorption diffuse readily across lipid membranes into acidified compartments (eg, the parietal cell canaliculus). The prodrug rapidly becomes protonated within the canaliculus and is concentrated more than 1000-fold by Henderson-Hasselbalch trapping (see Chapter 1). There, it rapidly undergoes a molecular conversion to the active form, a reactive thiophilic sulfenamide cation, which forms a covalent disulfide bond with the H+,K+ ATPase, irreversibly inactivating the enzyme. From a pharmacokinetic perspective, proton pump inhibitors are ideal drugs: they have a short serum half-life, they are concentrated and activated near their site of action, and they have a long duration of action. Pharmacodynamics In contrast to H2 antagonists, proton pump inhibitors inhibit both fasting and meal-stimulated secretion because they block the final common pathway of acid secretion, the proton pump. In standard doses, proton pump inhibitors inhibit 90-98% of 24-hour acid secretion (Figure 62-2). When administered at equivalent doses, the different agents show little difference in clinical efficacy. In a crossover study of patients receiving long-term therapy with all five proton pump inhibitors, the mean 24-hour intragastric pH varied from 3.3 (pantoprazole, 40 mg) to 4.0 (esomeprazole, 40 mg) and the mean number of hours the pH was higher than 4 varied from 10.1 (pantoprazole, 40 mg) to 14.0 (esomeprazole, 40 mg). Clinical Uses Gastroesophageal Reflux Disease (GERD) Proton pump inhibitors are the most effective agents for the treatment of nonerosive and erosive reflux disease, esophageal complications of reflux disease (peptic stricture or Barretts esophagus), and extraesophageal manifestations of reflux disease. Once-daily dosing provides effective symptom relief and tissue healing in 85-90% of patients; up to 15% of patients require twice-daily dosing. GERD symptoms recur in over 80% of patients within 6 months after discontinuation of a proton pump inhibitor. For patients with erosive esophagitis or esophageal complications, long-term daily maintenance therapy with a full-dose or half-dose proton pump inhibitor is usually needed. Many patients with nonerosive GERD may be treated successfully with intermittent courses of proton pump inhibitors or H2 antagonists taken as needed (on demand) for recurrent symptoms. In current clinical practice, many patients with symptomatic GERD are treated empirically with medications without prior endoscopy, ie, without knowledge of whether the patient has erosive or nonerosive reflux disease. Empiric treatment with proton pump inhibitors provides sustained symptomatic relief in 70-80% of patients, compared with 50-60% with H2 antagonists. Because of recent cost reductions, proton pump inhibitors are being used increasingly as first-line therapy for patients with symptomatic GERD. Sustained acid suppression with twice-daily proton pump inhibitors for at least 3 months is used to treat extraesophageal complications of reflux disease (asthma, chronic cough, laryngitis, and noncardiac chest pain). Peptic Ulcer Disease Compared with H2 antagonists, proton pump inhibitors afford more rapid symptom relief and faster ulcer healing for duodenal ulcers and, to a lesser extent, gastric ulcers. All the pump inhibitors heal more than 90% of duodenal ulcers within 4 weeks and a similar percentage of gastric ulcers within 6-8 weeks. H pylori-Associated Ulcers For H pylori-associated ulcers, there are two therapeutic goals: to heal the ulcer and to eradicate the organism. The most effective regimens for H pylori eradication are combinations of two antibiotics and a proton pump inhibitor. Proton pump inhibitors promote eradication of H pylori through several mechanisms: direct antimicrobial properties (minor) and—by raising intragastric pH—lowering the minimal inhibitory concentrations of antibiotics against H pylori. The best treatment regimen consists of a 14-day regimen of triple therapy: a proton pump inhibitor twice daily; clarithromycin, 500 mg twice daily; and either amoxicillin, 1 g twice daily, or metronidazole, 500 mg twice daily. After completion of triple therapy, the proton pump inhibitor should be continued once daily for a total of 4-6 weeks to ensure complete ulcer healing. Recently, 10 days of sequential treatment consisting on days 1-5 of a proton pump inhibitor twice daily plus amoxicillin, 1 g twice daily, and followed on days 6-10 by five additional days of a proton pump inhibitor twice daily, plus clarithromycin, 500 mg twice daily, and tinidazole, 500 mg twice daily, has been shown to be a highly effective treatment regimen. NSAID-Associated Ulcers For patients with ulcers caused by aspirin or other NSAIDs, either H2 antagonists or proton pump inhibitors provide rapid ulcer healing so long as the NSAID is discontinued; however continued use of the NSAID impairs ulcer healing. In patients with NSAID-induced ulcers who require continued NSAID therapy, treatment with a once- or twice-daily proton pump inhibitor more reliably promotes ulcer healing. Asymptomatic peptic ulceration develops in 10-20% of people taking frequent NSAIDs, and ulcer-related complications (bleeding, perforation) develop in 1-2% of persons per year. Proton pump inhibitors taken once daily are effective in reducing the incidence of ulcers and ulcer complications in patients taking aspirin or other NSAIDs. Prevention of Rebleeding from Peptic Ulcers In patients with acute gastrointestinal bleeding due to peptic ulcers, the risk of rebleeding from ulcers that have a visible vessel or adherent clot is increased. Rebleeding of this subset of high-risk ulcers is reduced significantly with proton pump inhibitors administered for 3-5 days either as high-dose oral therapy (eg, omeprazole, 40 mg orally twice daily) or as a continuous intravenous infusion. It is believed that an intragastric pH higher than 6 may enhance coagulation and platelet aggregation. The optimal dose of intravenous proton pump inhibitor needed to achieve and maintain this level of near-complete acid inhibition is unknown; however, initial bolus administration (80 mg) followed by constant infusion (8 mg/h) is commonly recommended. Nonulcer Dyspepsia Proton pump inhibitors have modest efficacy for treatment of nonulcer dyspepsia, benefiting 10-20% more patients than placebo. Despite their use for this indication, superiority to H2 antagonists (or even placebo) has not been conclusively demonstrated. Prevention of Stress-Related Mucosal Bleeding As discussed previously (see H2-Receptor Antagonists) proton pump inhibitors (given orally, by nasogastric tube, or by intravenous infusions) may be administered to reduce the risk of clinically significant stress-related mucosal bleeding in critically ill patients. The only proton pump inhibitor approved by the Food and Drug Administration (FDA) for this indication is an oral immediate-release omeprazole formulation, which is administered by nasogastric tube twice daily on the first day, then once daily. For patients with nasoenteric tubes, immediate-release omeprazole may be preferred to intravenous H2 antagonists or proton pump inhibitors because of comparable efficacy, lower cost, and ease of administration. For patients without a nasoenteric tube or with significant ileus, intravenous H2 antagonists are preferred to intravenous proton pump inhibitors because of their proven efficacy and lower cost. Although proton pump inhibitors are increasingly used, there are no controlled trials demonstrating efficacy or optimal dosing. Gastrinoma and Other Hypersecretory Conditions Patients with isolated gastrinomas are best treated with surgical resection. In patients with metastatic or unresectable gastrinomas, massive acid hypersecretion results in peptic ulceration, erosive esophagitis, and malabsorption. Previously, these patients required vagotomy and extraordinarily high doses of H2 antagonists, which still resulted in suboptimal acid suppression. With proton pump inhibitors, excellent acid suppression can be achieved in all patients. Dosage is titrated to reduce basal acid output to less than 5-10 mEq/h. Typical doses of omeprazole are 60-120 mg/d. Adverse Effects General Proton pump inhibitors are extremely safe. Diarrhea, headache, and abdominal pain are reported in 1-5% of patients, although the frequency of these events is only slightly increased compared with placebo. Proton pump inhibitors do not have teratogenicity in animal models; however, safety during pregnancy has not been established. Nutrition Acid is important in releasing vitamin B12 from food. A minor reduction in oral cyanocobalamin absorption occurs during proton pump inhibition, potentially leading to subnormal B12 levels with prolonged therapy. Acid also promotes absorption of food-bound minerals (iron, calcium, zinc); however, no mineral deficiencies have been reported with proton pump inhibitor therapy. Recent case-control studies have suggested a modest increase in the risk of hip fracture in patients taking proton pump inhibitors over a long term compared with matched controls. Although a causal relationship is unproven, proton pump inhibitors may reduce calcium absorption or inhibit osteoclast function. Pending further studies, patients who require long-term proton pump inhibitors—especially those with risk factors for osteoporosis—should have monitoring of bone density and should be provided calcium supplements. Respiratory and Enteric Infections Gastric acid is an important barrier to colonization and infection of the stomach and intestine from ingested bacteria. Increases in gastric bacterial concentrations are detected in patients taking proton pump inhibitors, which is of unknown clinical significance. Some studies have reported an increased risk of both community-acquired respiratory infections and nosocomial pneumonia among patients taking proton pump inhibitors. A small increased risk of enteric infections may exist in patients taking proton pump inhibitors, especially when traveling in underdeveloped countries. Hospitalized patients may have an increased risk for Clostridium difficile infection. Potential Problems Due to Increased Serum Gastrin Gastrin levels are regulated by intragastric acidity. Acid suppression alters normal feedback inhibition so that median serum gastrin levels rise 1.5- to 2-fold in patients taking proton pump inhibitors. Although gastrin levels remain within normal limits in most patients, they exceed 500 pg/mL (normal, The rise in serum gastrin levels in patients receiving long-term therapy with proton pump inhibitors raises a theoretical concern because gastrin may stimulate hyperplasia of ECL cells. In female rats given proton pump inhibitors for prolonged periods, gastric carcinoid tumors developed in areas of ECL hyperplasia. Although humans who take proton pump inhibitors for a long time may exhibit ECL hyperplasia in response to hypergastrinemia, carcinoid tumor formation has not been documented. At present, routine monitoring of serum gastrin levels is not recommended in patients receiving prolonged proton pump inhibitor therapy. Other Potential Problems Due to Decreased Gastric Acidity Among patients infected with H pylori, long-term acid suppression leads to increased chronic inflammation in the gastric body and decreased inflammation in the antrum. Concerns have been raised that increased gastric inflammation may accelerate gastric gland atrophy (atrophic gastritis) and intestinal metaplasia—known risk factors for gastric adenocarcinoma. A special FDA Gastrointestinal Advisory Committee concluded that there is no evidence that prolonged proton pump inhibitor therapy produces the kind of atrophic gastritis (multifocal atrophic gastritis) or intestinal metaplasia that is associated with increased risk of adenocarcinoma. Routine testing for H pylori is not recommended in patients who require long-term proton pump inhibitor therapy. Long-term proton pump inhibitor therapy is associated with the development of small benign gastric fundic-gland polyps in a small number of patients, which may disappear after stopping the drug and are of uncertain clinical signifi cance. Drug Interactions Decreased gastric acidity may alter absorption of drugs for which intragastric acidity affects drug bioavailability, eg, ketoconazole, itraconazole, digoxin, and atazanavir. All proton pump inhibitors are metabolized by hepatic P450 cytochromes, including CYP2C19 and CYP3A4. Because of the short half-lives of proton pump inhibitors, clinically significant drug interactions are rare. Omeprazole may inhibit the metabolism of warfarin, diazepam, and phenytoin. Esomeprazole also may decrease metabolism of diazepam. Lansoprazole may enhance clearance of theophylline. Rabeprazole and pantoprazole have no significant drug interactions. Mucosal Protective Agents The gastroduodenal mucosa has evolved a number of defense mechanisms to protect itself against the noxious effects of acid and pepsin. Both mucus and epithelial cell-cell tight junctions restrict back diffusion of acid and pepsin. Epithelial bicarbonate secretion establishes a pH gradient within the mucous layer in which the pH ranges from 7 at the mucosal surface to 1-2 in the gastric lumen. Blood flow carries bicarbonate and vital nutrients to surface cells. Areas of injured epithelium are quickly repaired by restitution, a process in which migration of cells from gland neck cells seals small erosions to rees Drugs in the Treatment of Gastrointestinal Disease Drugs in the Treatment of Gastrointestinal Disease Introduction Many of the drug groups discussed elsewhere in this book have important applications in the treatment of diseases of the gastrointestinal tract and other organs. Other groups are used almost exclusively for their effects on the gut; these are discussed in the following text according to their therapeutic uses. Drugs Used in Acid-Peptic Diseases Acid-peptic diseases include gastroesophageal reflux, peptic ulcer (gastric and duodenal), and stress-related mucosal injury. In all these conditions, mucosal erosions or ulceration arise when the caustic effects of aggressive factors (acid, pepsin, bile) overwhelm the defensive factors of the gastrointestinal mucosa (mucus and bicarbonate secretion, prostaglandins, blood flow, and the processes of restitution and regeneration after cellular injury). Over 90% of peptic ulcers are caused by infection with the bacterium Helicobacter pylori or by use of nonsteroidal anti-inflammatory drugs (NSAIDs). Drugs used in the treatment of acid-peptic disorders may be divided into two classes: agents that reduce intragastric acidity and agents that promote mucosal defense. Agents that Reduce Intragastric Acidity Physiology of Acid Secretion The parietal cell contains receptors for gastrin (CCK-B), histamine (H2), and acetylcholine (muscarinic, M3) (Figure 62-1). When acetylcholine (from vagal postganglionic nerves) or gastrin (released from antral G cells into the blood) bind to the parietal cell receptors, they cause an increase in cytosolic calcium, which in turn stimulates protein kinases that stimulate acid secretion from a H+,K+ ATPase (the proton pump) on the canalicular surface. In close proximity to the parietal cells are gut endocrine cells called enterochromaffin-like (ECL) cells. ECL cells also have receptors for gastrin and acetylcholine, which stimulate histamine release. Histamine binds to the H2 receptor on the parietal cell, resulting in activation of adenylyl cyclase, which increases intracellular cyclic adenosine monophosphate (cAMP) and activates protein kinases that stimulate acid secretion by the H+,K+ ATPase. In humans, it is believed that the major effect of gastrin upon acid secretion is mediated indirectly through the release of histamine from ECL cells rather than through direct parietal cell stimulation. In contrast, acetylcholine provides potent direct parietal cell stimulation. Antacids Antacids have been used for centuries in the treatment of patients with dyspepsia and acid-peptic disorders. They were the mainstay of treatment for acid-peptic disorders until the advent of H2-receptor antagonists and proton pump inhibitors. They continue to be used commonly by patients as nonprescription remedies for the treatment of intermittent heartburn and dyspepsia. Antacids are weak bases that react with gastric hydrochloric acid to form a salt and water. Their principal mechanism of action is reduction of intragastric acidity. After a meal, approximately 45 mEq/h of hydrochloric acid is secreted. A single dose of 156 mEq of antacid given 1 hour after a meal effectively neutralizes gastric acid for up to 2 hours. However, the acid-neutralization capacity among different proprietary formulations of antacids is highly variable, depending on their rate of dissolution (tablet versus liquid), water solubility, rate of reaction with acid, and rate of gastric emptying. Sodium bicarbonate (eg, baking soda, Alka Seltzer) reacts rapidly with hydrochloric acid (HCL) to produce carbon dioxide and sodium chloride. Formation of carbon dioxide results in gastric distention and belching. Unreacted alkali is readily absorbed, potentially causing metabolic alkalosis when given in high doses or to patients with renal insufficiency. Sodium chloride absorption may exacerbate fluid retention in patients with heart failure, hypertension, and renal insufficiency. Calcium carbonate (eg, Tums, Os-Cal) is less soluble and reacts more slowly than sodium bicarbonate with HCl to form carbon dioxide and calcium chloride (CaCl2). Like sodium bicarbonate, calcium carbonate may cause belching or metabolic alkalosis. Calcium carbonate is used for a number of other indications apart from its antacid properties (see Chapter 42). Excessive doses of either sodium bicarbonate or calcium carbonate with calcium-containing dairy products can lead to hypercalcemia, renal insufficiency , and metabolic alkalosis (milk-alkali syndrome). Formulations containing magnesium hydroxide or aluminum hydroxide react slowly with HCl to form magnesium chloride or aluminum chloride and water. Because no gas is generated, belching does not occur. Metabolic alkalosis is also uncommon because of the efficiency of the neutralization reaction. Because unabsorbed magnesium salts may cause an osmotic diarrhea and aluminum salts may cause constipation, these agents are commonly administered together in proprietary formulations (eg, Gelusil, Maalox, Mylanta) to minimize the impact on bowel function. Both magnesium and aluminum are absorbed and excreted by the kidneys. Hence, patients with renal insufficiency should not take these agents long-term. All antacids may affect the absorption of other medications by binding the drug (reducing its absorption) or by increasing intragastric pH so that the drugs dissolution or solubility (especially weakly basic or acidic drugs) is altered. Therefore, antacids should not be given within 2 hours of doses of tetracyclines, fluoroquinolones, itraconazole, and iron. H2-Receptor Antagonists From their introduction in the 1970s until the early 1990s, H2-receptor antagonists (commonly referred to as H2 blockers) were the most commonly prescribed drugs in the world (see Clinical Uses). With the recognition of the role of H pylori in ulcer disease (which may be treated with appropriate antibacterial therapy) and the advent of proton pump inhibitors, the use of prescription H2 blockers has declined markedly. Chemistry Pharmacokinetics Four H2 antagonists are in clinical use: cimetidine, ranitidine, famotidine, and nizatidine. All four agents are rapidly absorbed from the intestine. Cimetidine, ranitidine, and famotidine undergo first-pass hepatic metabolism resulting in a bioavailability of approximately 50%. Nizatidine has little first-pass metabolism. The serum half-lives of the four agents range from 1.1 to 4 hours; however, duration of action depends on the dose given (Table 62-1). H2 antagonists are cleared by a combination of hepatic metabolism, glomerular filtration, and renal tubular secretion. Dose reduction is required in patients with moderate to severe renal (and possibly severe hepatic) insufficiency. In the elderly, there is a decline of up to 50% in drug clearance as well as a significant reduction in volume of distribution. BID, twice daily; HS, bedtime. Clinical Uses H2-receptor antagonists continue to be prescribed but proton pump inhibitors (see below) are steadily replacing H2 antagonists for most clinical indications. However, the over-the-counter preparations are heavily used by the public. Gastroesophageal Reflux Disease (GERD) Patients with infrequent heartburn or dyspepsia (fewer than 3 times per week) may take either antacids or intermittent H2 antagonists. Because antacids provide rapid acid neutralization, they afford faster symptom relief than H2 antagonists. However, the effect of antacids is short-lived (1-2 hours) compared with H2 antagonists (6-10 hours). H2 antagonists may be taken prophylactically before meals in an effort to reduce the likelihood of heartburn. Frequent heartburn is better treated with twice-daily H2 antagonists (Table 62-1) or proton pump inhibitors. In patients with erosive esophagitis (approximately 50% of patients with GERD), H2 antagonists afford healing in less than 50% of patients; hence proton pump inhibitors are preferred because of their superior acid inhibition. Peptic Ulcer Disease Proton pump inhibitors have largely replaced H2 antagonists in the treatment of acute peptic ulcer disease. Nevertheless, H2 antagonists are still sometimes used. Nocturnal acid suppression by H2 antagonists affords effective ulcer healing in most patients with uncomplicated gastric and duodenal ulcers. Hence, all the agents may be administered once daily at bedtime, resulting in ulcer healing rates of more than 80-90% after 6-8 weeks of therapy. For patients with ulcers caused by aspirin or other NSAIDs, the NSAID should be discontinued. If the NSAID must be continued for clinical reasons despite active ulceration, a proton pump inhibitor should be given instead of an H2 antagonist to more reliably promote ulcer healing. For patients with acute peptic ulcers caused by H pylori, H2 antagonists no longer play a significant therapeutic role. H pylori should be treated with a 10- to 14-day course of therapy including a proton pump inhibitor and two antibiotics (see below). This regimen achieves ulcer healing and eradication of the infection in more than 90% of patients. For the minority of patients in whom H pylori cannot be successfully eradicated, H2 antagonists may be given daily at bedtime in half of the usual ulcer therapeutic dose to prevent ulcer recurrence (eg, ranitidine, 150 mg; famotidine, 20 mg). Nonulcer Dyspepsia H2 antagonists are commonly used as over-the-counter agents and prescription agents for treatment of intermittent dyspepsia not caused by peptic ulcer. However, benefit compared with placebo has never been convincingly demonstrated. Prevention of Bleeding from Stress-Related Gastritis Clinically important bleeding from upper gastrointestinal erosions or ulcers occurs in 1-5% of critically ill patients as a result of impaired mucosal defense mechanisms caused by poor perfusion. Although most critically ill patients have normal or decreased acid secretion, numerous studies have shown that agents that increase intragastric pH (H2 antagonists or proton pump inhibitors) reduce the incidence of clinically significant bleeding. However, the optimal agent is uncertain at this time. For patients without a nasoenteric tube or with significant ileus, intravenous H2 antagonists are preferable over intravenous proton pump inhibitors because of their proven efficacy and lower cost. Continuous infusions of H2 antagonists are generally preferred to bolus infusions because they achieve more consistent, sustained elevation of intragastric pH. Adverse Effects H2 antagonists are extremely safe drugs. Adverse effects occur in less than 3% of patients and include diarrhea, headache, fatigue, myalgias, and constipation. Some studies suggest that intravenous H2 antagonists (or proton pump inhibitors) may increase the risk of nosocomial pneumonia in critically ill patients. Mental status changes (confusion, hallucinations, agitation) may occur with administration of intravenous H2 antagonists, especially in patients in the intensive care unit who are elderly or who have renal or hepatic dysfunction. These events may be more common with cimetidine. Mental status changes rarely occur in ambulatory patients. Cimetidine inhibits binding of dihydrotestosterone to androgen receptors, inhibits metabolism of estradiol, and increases serum prolactin levels. When used long-term or in high doses, it may cause gynecomastia or impotence in men and galactorrhea in women. These effects are specific to cimetidine and do not occur with the other H2 antagonists. Although there are no known harmful effects on the fetus, H2 antagonists cross the placenta. Therefore, they should not be administered to pregnant women unless absolutely necessary. The H2 antagonists are secreted into breast milk and may therefore affect nursing infants. H2 antagonists may rarely cause blood dyscrasias. Blockade of cardiac H2 receptors may cause bradycardia, but this is rarely of clinical significance. Rapid intravenous infusion may cause bradycardia and hypotension through blockade of cardiac H2 receptors; therefore, intravenous injections should be given over 30 minutes. H2 antagonists rarely cause reversible abnormalities in liver chemistry. Drug Interactions Cimetidine interferes with several important hepatic cytochrome P450 drug metabolism pathways, including those catalyzed by CYP1A2, CYP2C9, CYP2D6, and CYP3A4 (see Chapter 4). Hence, the half-lives of drugs metabolized by these pathways may be prolonged. Ranitidine binds 4-10 times less avidly than cimetidine to cytochrome P450. Negligible interaction occurs with nizatidine and famotidine. H2 antagonists compete with creatinine and certain drugs (eg, procainamide) for renal tubular secretion. All of these agents except famotidine inhibit gastric first-pass metabolism of ethanol, especially in women. Although the importance of this is debated, increased bioavailability of ethanol could lead to increased blood ethanol levels. Proton Pump Inhibitors Since their introduction in the late 1980s, these efficacious acid inhibitory agents have assumed the major role for the treatment of acid-peptic disorders. Proton pump inhibitors (PPIs) are now among the most widely prescribed drugs worldwide due to their outstanding efficacy and safety. Chemistry Pharmacokinetics Five proton pump inhibitors are available for clinical use: omeprazole, lansoprazole, rabeprazole, pantoprazole, and esomeprazole. All are substituted benzimidazoles that resemble H2 antagonists in structure (Figure 62-3) but have a completely different mechanism of action. Omeprazole is a racemic mixture of R- and S-isomers. Esomeprazole is the S-isomer of omeprazole. All are available in oral formulations. Esomeprazole and pantoprazole are also available in intravenous formulations . Proton pump inhibitors are administered as inactive prodrugs. To protect the acid-labile prodrug from rapid destruction within the gastric lumen, oral products are formulated for delayed release as acid-resistant, enteric-coated capsules or tablets. After passing through the stomach into the alkaline intestinal lumen, the enteric coatings dissolve and the prodrug is absorbed. For children or patients with dysphagia or enteral feeding tubes, capsules may be opened and the microgranules mixed with apple or orange juice or mixed with soft foods (eg, applesauce). Lansoprazole is also available as a tablet formulation that disintegrates in the mouth, or it may be mixed with water and administered via oral syringe or enteral tube. Omeprazole is also available as a powder formulation (capsule or packet) that contains sodium bicarbonate (1100-1680 mg NaHCO3 ; 304-460 mg of sodium) to protect the naked (non-enteric-coated) drug from acid degradation. When administered on an empty stomach by m outh or enteral tube, this immediate-release suspension results in rapid omeprazole absorption (Tmax The proton pump inhibitors are lipophilic weak bases (pKa 4-5) and after intestinal absorption diffuse readily across lipid membranes into acidified compartments (eg, the parietal cell canaliculus). The prodrug rapidly becomes protonated within the canaliculus and is concentrated more than 1000-fold by Henderson-Hasselbalch trapping (see Chapter 1). There, it rapidly undergoes a molecular conversion to the active form, a reactive thiophilic sulfenamide cation, which forms a covalent disulfide bond with the H+,K+ ATPase, irreversibly inactivating the enzyme. From a pharmacokinetic perspective, proton pump inhibitors are ideal drugs: they have a short serum half-life, they are concentrated and activated near their site of action, and they have a long duration of action. Pharmacodynamics In contrast to H2 antagonists, proton pump inhibitors inhibit both fasting and meal-stimulated secretion because they block the final common pathway of acid secretion, the proton pump. In standard doses, proton pump inhibitors inhibit 90-98% of 24-hour acid secretion (Figure 62-2). When administered at equivalent doses, the different agents show little difference in clinical efficacy. In a crossover study of patients receiving long-term therapy with all five proton pump inhibitors, the mean 24-hour intragastric pH varied from 3.3 (pantoprazole, 40 mg) to 4.0 (esomeprazole, 40 mg) and the mean number of hours the pH was higher than 4 varied from 10.1 (pantoprazole, 40 mg) to 14.0 (esomeprazole, 40 mg). Clinical Uses Gastroesophageal Reflux Disease (GERD) Proton pump inhibitors are the most effective agents for the treatment of nonerosive and erosive reflux disease, esophageal complications of reflux disease (peptic stricture or Barretts esophagus), and extraesophageal manifestations of reflux disease. Once-daily dosing provides effective symptom relief and tissue healing in 85-90% of patients; up to 15% of patients require twice-daily dosing. GERD symptoms recur in over 80% of patients within 6 months after discontinuation of a proton pump inhibitor. For patients with erosive esophagitis or esophageal complications, long-term daily maintenance therapy with a full-dose or half-dose proton pump inhibitor is usually needed. Many patients with nonerosive GERD may be treated successfully with intermittent courses of proton pump inhibitors or H2 antagonists taken as needed (on demand) for recurrent symptoms. In current clinical practice, many patients with symptomatic GERD are treated empirically with medications without prior endoscopy, ie, without knowledge of whether the patient has erosive or nonerosive reflux disease. Empiric treatment with proton pump inhibitors provides sustained symptomatic relief in 70-80% of patients, compared with 50-60% with H2 antagonists. Because of recent cost reductions, proton pump inhibitors are being used increasingly as first-line therapy for patients with symptomatic GERD. Sustained acid suppression with twice-daily proton pump inhibitors for at least 3 months is used to treat extraesophageal complications of reflux disease (asthma, chronic cough, laryngitis, and noncardiac chest pain). Peptic Ulcer Disease Compared with H2 antagonists, proton pump inhibitors afford more rapid symptom relief and faster ulcer healing for duodenal ulcers and, to a lesser extent, gastric ulcers. All the pump inhibitors heal more than 90% of duodenal ulcers within 4 weeks and a similar percentage of gastric ulcers within 6-8 weeks. H pylori-Associated Ulcers For H pylori-associated ulcers, there are two therapeutic goals: to heal the ulcer and to eradicate the organism. The most effective regimens for H pylori eradication are combinations of two antibiotics and a proton pump inhibitor. Proton pump inhibitors promote eradication of H pylori through several mechanisms: direct antimicrobial properties (minor) and—by raising intragastric pH—lowering the minimal inhibitory concentrations of antibiotics against H pylori. The best treatment regimen consists of a 14-day regimen of triple therapy: a proton pump inhibitor twice daily; clarithromycin, 500 mg twice daily; and either amoxicillin, 1 g twice daily, or metronidazole, 500 mg twice daily. After completion of triple therapy, the proton pump inhibitor should be continued once daily for a total of 4-6 weeks to ensure complete ulcer healing. Recently, 10 days of sequential treatment consisting on days 1-5 of a proton pump inhibitor twice daily plus amoxicillin, 1 g twice daily, and followed on days 6-10 by five additional days of a proton pump inhibitor twice daily, plus clarithromycin, 500 mg twice daily, and tinidazole, 500 mg twice daily, has been shown to be a highly effective treatment regimen. NSAID-Associated Ulcers For patients with ulcers caused by aspirin or other NSAIDs, either H2 antagonists or proton pump inhibitors provide rapid ulcer healing so long as the NSAID is discontinued; however continued use of the NSAID impairs ulcer healing. In patients with NSAID-induced ulcers who require continued NSAID therapy, treatment with a once- or twice-daily proton pump inhibitor more reliably promotes ulcer healing. Asymptomatic peptic ulceration develops in 10-20% of people taking frequent NSAIDs, and ulcer-related complications (bleeding, perforation) develop in 1-2% of persons per year. Proton pump inhibitors taken once daily are effective in reducing the incidence of ulcers and ulcer complications in patients taking aspirin or other NSAIDs. Prevention of Rebleeding from Peptic Ulcers In patients with acute gastrointestinal bleeding due to peptic ulcers, the risk of rebleeding from ulcers that have a visible vessel or adherent clot is increased. Rebleeding of this subset of high-risk ulcers is reduced significantly with proton pump inhibitors administered for 3-5 days either as high-dose oral therapy (eg, omeprazole, 40 mg orally twice daily) or as a continuous intravenous infusion. It is believed that an intragastric pH higher than 6 may enhance coagulation and platelet aggregation. The optimal dose of intravenous proton pump inhibitor needed to achieve and maintain this level of near-complete acid inhibition is unknown; however, initial bolus administration (80 mg) followed by constant infusion (8 mg/h) is commonly recommended. Nonulcer Dyspepsia Proton pump inhibitors have modest efficacy for treatment of nonulcer dyspepsia, benefiting 10-20% more patients than placebo. Despite their use for this indication, superiority to H2 antagonists (or even placebo) has not been conclusively demonstrated. Prevention of Stress-Related Mucosal Bleeding As discussed previously (see H2-Receptor Antagonists) proton pump inhibitors (given orally, by nasogastric tube, or by intravenous infusions) may be administered to reduce the risk of clinically significant stress-related mucosal bleeding in critically ill patients. The only proton pump inhibitor approved by the Food and Drug Administration (FDA) for this indication is an oral immediate-release omeprazole formulation, which is administered by nasogastric tube twice daily on the first day, then once daily. For patients with nasoenteric tubes, immediate-release omeprazole may be preferred to intravenous H2 antagonists or proton pump inhibitors because of comparable efficacy, lower cost, and ease of administration. For patients without a nasoenteric tube or with significant ileus, intravenous H2 antagonists are preferred to intravenous proton pump inhibitors because of their proven efficacy and lower cost. Although proton pump inhibitors are increasingly used, there are no controlled trials demonstrating efficacy or optimal dosing. Gastrinoma and Other Hypersecretory Conditions Patients with isolated gastrinomas are best treated with surgical resection. In patients with metastatic or unresectable gastrinomas, massive acid hypersecretion results in peptic ulceration, erosive esophagitis, and malabsorption. Previously, these patients required vagotomy and extraordinarily high doses of H2 antagonists, which still resulted in suboptimal acid suppression. With proton pump inhibitors, excellent acid suppression can be achieved in all patients. Dosage is titrated to reduce basal acid output to less than 5-10 mEq/h. Typical doses of omeprazole are 60-120 mg/d. Adverse Effects General Proton pump inhibitors are extremely safe. Diarrhea, headache, and abdominal pain are reported in 1-5% of patients, although the frequency of these events is only slightly increased compared with placebo. Proton pump inhibitors do not have teratogenicity in animal models; however, safety during pregnancy has not been established. Nutrition Acid is important in releasing vitamin B12 from food. A minor reduction in oral cyanocobalamin absorption occurs during proton pump inhibition, potentially leading to subnormal B12 levels with prolonged therapy. Acid also promotes absorption of food-bound minerals (iron, calcium, zinc); however, no mineral deficiencies have been reported with proton pump inhibitor therapy. Recent case-control studies have suggested a modest increase in the risk of hip fracture in patients taking proton pump inhibitors over a long term compared with matched controls. Although a causal relationship is unproven, proton pump inhibitors may reduce calcium absorption or inhibit osteoclast function. Pending further studies, patients who require long-term proton pump inhibitors—especially those with risk factors for osteoporosis—should have monitoring of bone density and should be provided calcium supplements. Respiratory and Enteric Infections Gastric acid is an important barrier to colonization and infection of the stomach and intestine from ingested bacteria. Increases in gastric bacterial concentrations are detected in patients taking proton pump inhibitors, which is of unknown clinical significance. Some studies have reported an increased risk of both community-acquired respiratory infections and nosocomial pneumonia among patients taking proton pump inhibitors. A small increased risk of enteric infections may exist in patients taking proton pump inhibitors, especially when traveling in underdeveloped countries. Hospitalized patients may have an increased risk for Clostridium difficile infection. Potential Problems Due to Increased Serum Gastrin Gastrin levels are regulated by intragastric acidity. Acid suppression alters normal feedback inhibition so that median serum gastrin levels rise 1.5- to 2-fold in patients taking proton pump inhibitors. Although gastrin levels remain within normal limits in most patients, they exceed 500 pg/mL (normal, The rise in serum gastrin levels in patients receiving long-term therapy with proton pump inhibitors raises a theoretical concern because gastrin may stimulate hyperplasia of ECL cells. In female rats given proton pump inhibitors for prolonged periods, gastric carcinoid tumors developed in areas of ECL hyperplasia. Although humans who take proton pump inhibitors for a long time may exhibit ECL hyperplasia in response to hypergastrinemia, carcinoid tumor formation has not been documented. At present, routine monitoring of serum gastrin levels is not recommended in patients receiving prolonged proton pump inhibitor therapy. Other Potential Problems Due to Decreased Gastric Acidity Among patients infected with H pylori, long-term acid suppression leads to increased chronic inflammation in the gastric body and decreased inflammation in the antrum. Concerns have been raised that increased gastric inflammation may accelerate gastric gland atrophy (atrophic gastritis) and intestinal metaplasia—known risk factors for gastric adenocarcinoma. A special FDA Gastrointestinal Advisory Committee concluded that there is no evidence that prolonged proton pump inhibitor therapy produces the kind of atrophic gastritis (multifocal atrophic gastritis) or intestinal metaplasia that is associated with increased risk of adenocarcinoma. Routine testing for H pylori is not recommended in patients who require long-term proton pump inhibitor therapy. Long-term proton pump inhibitor therapy is associated with the development of small benign gastric fundic-gland polyps in a small number of patients, which may disappear after stopping the drug and are of uncertain clinical signifi cance. Drug Interactions Decreased gastric acidity may alter absorption of drugs for which intragastric acidity affects drug bioavailability, eg, ketoconazole, itraconazole, digoxin, and atazanavir. All proton pump inhibitors are metabolized by hepatic P450 cytochromes, including CYP2C19 and CYP3A4. Because of the short half-lives of proton pump inhibitors, clinically significant drug interactions are rare. Omeprazole may inhibit the metabolism of warfarin, diazepam, and phenytoin. Esomeprazole also may decrease metabolism of diazepam. Lansoprazole may enhance clearance of theophylline. Rabeprazole and pantoprazole have no significant drug interactions. Mucosal Protective Agents The gastroduodenal mucosa has evolved a number of defense mechanisms to protect itself against the noxious effects of acid and pepsin. Both mucus and epithelial cell-cell tight junctions restrict back diffusion of acid and pepsin. Epithelial bicarbonate secretion establishes a pH gradient within the mucous layer in which the pH ranges from 7 at the mucosal surface to 1-2 in the gastric lumen. Blood flow carries bicarbonate and vital nutrients to surface cells. Areas of injured epithelium are quickly repaired by restitution, a process in which migration of cells from gland neck cells seals small erosions to rees

Essay example --

The Red Farm Power is a great tool, but like the hammer it can build and destroy civilizations. This is the theme and lesson that I learned from George Orwell’s classic novel, Animal Farm. It is believed, and can be notably seen in the past, that many great people, like Julius Cesar and Napoleon, become dangerous and corrupt under vast amounts of power. Both wanted to own the world and extend the wealth of their country but ended up evil in the eyes of many. In history there seems to be a pattern of people at the top, the kings and rulers, falling to their deaths. These type of situations usually happen because the "lower classes" becomes irrelevant and has nothing in their lives. They see the king with all this power and realize that power can bring them happiness as well. Yet Having so much power is not always a good thing. In George Orwell’s novel, Animal Farm, a scary depiction of life in what we can assume to be a corruption of Socialist Ideals, in other words the "Soviet Union", is played out. In the novel personification is used on farm animals. The animals can talk and communicate, think, and even have feeling towards each other as if they were human. In the novel, George Orwell created a character named Napoleon. He is a pig who emerges as the leader of Animal Farm after the rebellion, and in many ways he is has the characteristics of the Soviet Leader, Joseph Stalin. In the begging he seems to be a good leader; unfortunately like history as proven before, he is eventually overcome in greed and a desire for power. In real life this is how Joseph Stalin became, after suspecting many people in his empire to be followers of Trotsky he became a very evil man. In real life Lion Trotsky and Joseph Stalin where political ... ...apoleons farm with fake bank notes, this sparks a war and blood is shed all over. Many animals die but despite the loss, Napoleons farm wins. The war is once again blamed on Snowball. The last significant event that leads to Napoleon's complete communist control is the killing of Boxer. With Boxer out of the picture, Napoleon ruled the farm with his dogs by his side, and the farm was back to how it began, except instead of humans controlling, the pigs and dogs did. Power is a great tool, but like the hammer it can build and destroy civilizations. To me nothing summarizes this novel better. The novel has enlightened me on the history of Soviet Union and how it was created and ran as a country. Till I read this book i had never heard of Lion Trotsky. Over all George Orwell's classic novel, Animal Farm was a great book and I loved readying it.

Discuss Austen(TM)s use of Mr Elliot in Persuasion

Austen uses Mr Elliot in various ways in Persuasion, this ranges from gaining an insight into other people's characters to contributing to the romance genre. Austen mainly uses Mr Elliot as a plot device in Book Two of the novel after Anne's arrival in Bath. The use of Mr Elliot's character can be tied into most of the major themes of the novel. The first mention of Mr Elliot in Persuasion is in the fist chapter of Book One. We find out that he is the heir presumptive to the Baronetcy, through Sir Walter who is reading the Baronetage. We can see that this is important to Sir Walter as he has added, â€Å"Heir presumptive, William Walter Elliot, Esq.† to the pages in the book referring to the Elliot's. This shows how class conscious Sir Walter is, it is blatantly obvious that Austen is ridiculing Sir Walter for being too class conscious. However later in the novel we see that whilst she does not approve of how class conscious Sir Walter is, Austen is still a woman of her time and we see that she is class conscious, through Anne's reactions, but not to the degree that Sir Walter is. In the same chapter we also find out more about Mr Elliot's past relationship with the Elliot family, in particular with Elizabeth and Sir Walter, to an extent. We see that Mr Elliot has disappointed her, â€Å"the heir presumptive †¦ had disappointed her† even though she had â€Å"found him extremely agreeable†. However instead of marrying Elizabeth, Mr Elliot sought independence and married â€Å"a rich woman of inferior birth.† This leads to all acquaintance between the ceasing as Mr Elliot had slighted Sir Walter and had â€Å"shewn himself as unsolicitous of being longer noticed by the family†. The next time we meet Mr Elliot is in the last chapter of Book One, where Anne and the Musgroves are in Lyme with Captain Wentworth. This chapter is where Mr Elliot sees Anne for the first time and where he is first seen as a potential rival for Anne's attention and affection, â€Å"Anne's face caught his eye, and he looked at her with a degree of earnest admiration†. Wentworth in turn notices how Mr Elliot looks at Anne and even he can â€Å"see something like Anne Elliot again†. Mr Elliot paying attention to Anne shows that se is once again in â€Å"bloom†. In this chapter through Anne and the others in Lyme that Mr Elliot is in mourning, therefore his wife has only died relatively recently. When the ‘mystery gentleman' is identified as Mr Elliot by the party in Lyme, we see that Austen highlights Mary's class snobbery. We next see Mr Elliot in Chapter Three of Book Two, however the reaction to him is much more positive than it was in the first book. We see that despite his previous grievances against them Elizabeth and Sir Walter readily forgive Mr Elliot and are even happy to renew their acquaintance. In this chapter we see that the relationship between Mr Elliot and Anne improves and we see that he is clearly attracted to her. This is where the possibility of Mr Elliot standing as a rival against Wentworth for Anne's affections becomes a reality. In the next chapter Austen uses Mr Elliot to show how fickle Lady Russell is. We see here that she feels that he could not be â€Å"a more agreeable or estimable man† and that â€Å"Everything united in him; good understanding, correct opinions, knowledge of the world, and a warm heart†. This directly contrast her feeling in Chapter Fourteen where she states that â€Å"he is a man whom [she has] no wish to see† and that he had â€Å"left a very strong impression in his disfavour† with her when he declined to be â€Å"on cordial terms with the head of his family†. Here we also see that Mr Elliot is not as class conscious as Sir Walter and Elizabeth but he is more class conscious than Anne. In the next chapters Mr Elliot becomes even more of an obstacle in Anne and Wentworth's relationship. We see what Anne's opinion of him is; she thinks that whilst â€Å"Mr Elliot is an exceedingly agreeable man† he was â€Å"too generally agreeable†. This shows how shrewd Anne is, compared with the rest of her family and her close friends. Austen uses Mr Elliot more in the second half of the novel in order to distract Anne's attention away from Wentworth. This can be seen in Chapter Twenty during the concert held for the benefit of a person patronised by Lady Dalrymple. We see that Mr Elliot successfully monopolises a lot of Anne's time, which in turn makes Wentworth jealous. Wentworth now knows that he is still in love with Anne due to the attention she is receiving from Mr Elliot, but again due to the obstacle Mr Elliot presents he can not make his feelings known to Anne. However after Mrs Smith unmasks Mr Elliot for Anne after the concert, we see him for who he truly is. Here Wentworth and Mr Elliot can be compared and you can clearly see who the better person is out of the two. Wentworth is everything that Mr Elliot is not, for example Wentworth is open and spontaneous whereas Mr Elliot is polished and conceals his emotions. Another example where the two can be compared is when Wentworth helps Mrs Smith when Mr Elliot deserted her in her time of need after the death of her husband. Here Austen clearly wants to show the differences between the two characters, and it highlights how Wentworth is from a lower class and has made his own fortune through hard work and how Mr Elliot stands to inherit his fortune whilst not even being half the man Wentworth is. In conclusion it could be said that Mr Elliot is of vital significance to the novel and that Austen uses him to further the plot, especially between Anne and Wentworth. He is used to show the characters and the readers that even though he is from the upper classes it does not mean that he is better than any one else. This brings up the theme of the changing ideal of the gentlemen in Persuasion. Austen also uses him throughout the novel in relation to the major themes, for example family as well as love.