Wednesday, July 8, 2020
<h1> Who's Concerned About Harry Potter Essay Topics Ideas and Why You Need to be Paying Attention </h1> <h2>What's Really Going on with Harry Potter Essay Topics Ideas </h2> <p>Unacademic is any sort of examination that shows up from places like wikipedia or google. When you have sifted through things, hit books searching for significant information. Contrasted with different sorts, such a work is viewed as a difficult undertaking since it's not just a portrayal. Another basic thing is identified with the essence of the subject. </p> <p>If you are mentioned to make this sort out of paper, there are numerous measurements that merit considering. Your psyche could be loaded up with every one of these potential outcomes you don't comprehend where to start. Attempt to make your errand simpler by settling regarding a matter of intrigue. Whichever case of a discourse subject you are probably going to pick, it will lead you to finish triumph! </p> <p>There's, unmistakably, a cutoff on the scope of pages even our best authors can deliver with a squeezing cutoff time, however for the most part, we can fulfill all the customers looking for dire help. Welcome to keep in contact by methods for your paper essayist controlling everything. The creator shows the assortment of strategies by which the minimized fall prisoner to adversity just since they are naturally introduced to bring down areas of the general public. </p> <h2> What Does Harry Potter Essay Topics Ideas Mean? </h2> <p>It isn't imperative to us, regardless of whether you're excessively occupied at work focusing on an enthusiasm undertaking, or essentially wore out on an apparently interminable stream of assignments. You need to incorporate all your exploration sources in a book index. Therefore, it's required to structure new clinical projects. Additionally, make certain to search out unmistakable highlights at different degrees of explorati on. </p> <p>It's much better to utilize peer-checked on articles and logical distributions since they give pertinent subtleties. It's acceptable as it is unsurprising. Select the one which you like best, and you'll compose an unbelievable paper! Regardless of whether this paper should be mocking, we have to observe the main characteristics of this style. </p> <p>After you have themes to pick from, it is fundamental that you pick one which you can expound on serenely. Picking your point is just the start. In the first place, experience the essentials. Conceptualize contemplations and make notes. </p> <p>Remember about the span of the paper and be certain that you have adequate words to handle a picked point or, in all likelihood limited it down. Investigating all the different perspectives and remembering them for your article expands the bore of your composition by acquiring your paper progressively complete and nuanced. </p> <p>The net is fundamental asset for assessment paper themes. When you've settled on an interpretive article subject, you will in all likelihood require a few systems about how to sort out the method for composing. The really stunning thing about our site is that you may locate a lot of fascinating tips that will make you consider what paper you'd prefer to compose. </p> <p>You might want your proposition to be completely clear and to precisely set up the rest of your exposition. The proposition will uncover the peruser accurately where you stand. Your proposal has become the most significant sentence in your powerful exposition. Rehash your proposal and don't present new thoughts. </p> <p>Also, you should pick cutting-edge sources since they offer you the most recent subtleties on your point. In this manner, don't be hesitant to counsel her or him on the off chance that you stuck when settling on a subject. Finding a strong theme is only one of the most urgent strides for composing any type of paper. In case you're still somewhat stuck or befuddled about how to pick the ideal examination paper point, I've created a rundown of 50 subject thoughts that will get you out. </p>
Sunday, June 28, 2020
<h1>College Papers - What Are They?</h1><p>College papers can be a genuine test, yet you can begin to get some thought of the sorts of papers that they are utilized for. Here is a breakdown of a portion of the various kinds of school papers, and a couple of ways that you can get them started.</p><p></p><p>Papers in science and math incorporate lab reports, material science reports, and analytics or logarithmic reports. These sorts of papers are a simple begin to kick you off. In the event that you are a decent understudy and have a set measure of cash you can purchase the entirety of your papers from a book. Ensure that you contrast costs and alternatives with locate the best cost. Books will in general be more costly than some other alternative, so ensure that you won't overspend on these.</p><p></p><p>As you come you will get more science papers, and your new classes will incorporate more classes that incorporate the mes, for example, science, and science. This is an incredible method to kick you off with some genuine science, science, and material science. This sort of paper will likewise incorporate a lab report that really expounds. This permits you to compose something that is all your own, rather than another person's words.</p><p></p><p>Paper works incorporates labs, test papers, and reports. This is an extraordinary alternative for the individuals who have been dealing with a task for some time, yet at the same time need a touch of work done. By and by, this is an incredible alternative for understudies who need to attend a university however need more cash to pay for everything. This paper is extremely easy to peruse and comprehend. The main thing to remember is that occasionally the appropriate response sheets will be distributed on the web. You will have the option to download them to use.</p><p></p><p>All of the paper types originate fro m various individuals, and you should pick the best paper for your requirements. Now and again the correct paper for your task will be unique in relation to the paper that different understudies are utilizing. Utilize the exhortation that you get, and attempt to be predictable with each paper that you use.</p><p></p><p>One of the primary things that you have to do is to make sense of what sort of paper you need to begin with. This will enable you to recognize what your choices are and whether you will be effective or not. It very well may be difficult to make sense of where to begin, however with the tips that we give you, you ought to have the option to make this choice.</p><p></p><p>While you are doing this you will likewise need to locate the best paper out there. You should see whether it is the best paper for you, or on the off chance that it is a decent alternative. These are the kind of tips that you will discover in our site, s o use them to locate the correct paper for you.</p>
Monday, June 15, 2020
<h1>Get the Best Review From Premiumessays Reviews</h1><p>Premiumessays surveys are another word for suggestions. These organizations give various apparatuses to you to settle on the correct choice. As a client, I figure you ought to have the option to utilize this in the most ideal manner possible.</p><p></p><p>Premiumessays surveys will assist you with choosing if they merit getting. This is a business which was established by individuals who are the two guardians. The primary focal point of their administrations is to assist guardians with discovering youngster care. They utilize the word 'survey' in their name. They have a rundown of their surveys, which they get from others, utilizing the word 'review'.</p><p></p><p>Reviews are extraordinary for your advantage since you can get a perspective on how others feel about a specific item. In any case, before you read any surveys you have to do some exploration on the or ganization. Peruse the total surveys before you begin perusing the one you need to peruse. More often than not, it appears that the awful audits are composed by individuals who have not done any exploration. You have to discover reality with regards to the administration before you decide.</p><p></p><p>Premiumessays audits are accessible on the web. You can decide to either visit their site or check their survey segment in the different sites. There are some different destinations which additionally offer to give audits. Notwithstanding, a portion of these surveys are composed by representatives who are as yet working at the company.</p><p></p><p>All these destinations have a free participation to make the most of their audit. So as to utilize this, you simply need to type the watchword (premiumessays surveys) in the pursuit box of a particular site. A portion of the locales likewise have an assistance segment, where you can pose the s pecialists about any inquiries you may have.</p><p></p><p>However, there are a few things you ought to recollect when you pick Premiumessays surveys. Try not to believe a lot of the remarks posted by the staff individuals. Check the notoriety of the organization before you get a free participation. This will assist you with knowing whether you can trust the review.</p><p></p><p>It is extremely imperative to see if you are getting the best arrangement with Premiumessays. In the event that you get a free participation, at that point you won't need to pay anything. You can along these lines center around your determination of the administration. Toward the day's end, it is about quality and convenience.</p>
Friday, June 5, 2020
Topics For Economics Research Paper - How to Do itMost students will often spend most of their time doing topics for economics research paper. However, these two topics have some differences when it comes to the topic you use to write your paper. Here are some suggestions on how to do that.Students should take time to write down their ideas before beginning the paper. That way, they can then go back and rewrite the same ideas with different angles in their head before actually writing the paper. When students do this, they can put their ideas into words that will help them to see how these topics relate to each other. They can go over each topic until they understand it in their head.However, if you're going to use international finance as your main topic, then you should rewrite the main ideas in a different way. Here are some examples of topics for economics research paper. Of course, the order is important, too.In this article, we discussed the topic of currency rate. The topic wa s used to write a topic for economics research paper because the currency rate is one of the most important topics that students study. Currency rates affect many different aspects of the economy.Another way of looking at the topic is to look at how the international money market works. You may also want to look at how the banking system works, as well as the history of the banks.Finally, it's important to look at the use of the commodities that you study. Do you look at agriculture, finance, or transportation?Other than these three topics, the topics for economics research papers often have to be thought about, but are not quite written yet. But, they are very important to understand before you begin writing your paper.Some topics for economics research paper that I wrote to include the topic of global macroeconomics, the topics of economics research paper, and international finance. These topics may be difficult to do, but I have found that the more I put my ideas into words, the easier it becomes.
Monday, June 1, 2020
Alberty v. United States (Essay Sample) Content: Alberty v. United States - D 1896; 162 U.S. 499; 231NameInstitution AffiliationAlberty v. United States - D 1896; 162 U.S. 499; 231This was a case involving the Defendant who was a Cherokee Negro and who was known by both his DadÃ ¢Ã¢â ¬s name of Burns and that of his former master, Alberty. He was sentenced for the murder of Phil Duncan at the Cherokee Nation situated in the Indian Terrain. The impeachment claimed that the offense was committed on 15th may 1879, but evidence showed that it was engaged in a year ahead, that was in 1880.The defendant sued out a court order upon the announcement of death judgment. The Defendant assigned a want of jurisdiction in the court and some faults in the charge to the bench of judges connected with the law of homicide. The Defendant extrapolated to be strained from the flight of the alleged.It was noted that the query of this law in this scenario demanded to be given a primary consideration. Although Alberty was a Negro born i n slavery and therefore not a native Indian, he was recognized as a citizen of the Cherokee entitled by the ninth article of the 1866 Treaty. Under the 1866 Treaty, the Cherokee Nation agreed to eradicate slavery and granted that all freedmen liberated by intentional acts of the by-laws as well as all free colored persons are now recognized as residents. Besides, those who were in the country at the inauguration of the Rebellion and now residing within or those who may return within a period of six months will have all the freedoms of the native Cherokees. Though this article provides him with the rights of a native Cherokee, it did not guarantee him Indian citizenship or pardon him from role to the criminal decrees of the United States.The deceased was recognized by name as Duncan. He was the unlawful child of a Choctaw Indian, by a colored mother, who was not his companion, but a slave in the Cherokee State. The mother was a Negro slave and therefore, the son was treated as a Negr o by birth and not a Choctaw Indian. There is an additional reason for this in the fact that he was an illegitimate child and took the status of the mother as previously ruled in Williamson v. Daniel, and Fowler v. Merrill cases.The Accused went to the Cherokee Nation when he turned 17 years old and married a freed woman who was a Cherokee Citizen. Though the Accused was married to a Cherokee citizen, it did not confer upon him the freedoms and rights of Cherokee citizenship, beyond that of residing and holding personal property in the Cherokee Nation. The law courts of the United States cannot entitle jurisdiction over such persons in crime or civil issues. Such people are also not allowed to taking part in any election activities. Therefore, for the laws of the United States to be applied, the Accused had to be treated as a citizen of the Cherokee Nation not an Indian and the Plaintiff as a colored citizen of the United States. The court also ruled out that, the general laws of th e United States shall extend to cover crimes in the Indian Nation, but these laws will not apply to offences committed by one Indian against a person or property of another Indian. The law will not apply to an Indian committing any offense in the Indian Republic who was penalized by the Indian legislation of the tribe. The law will not apply to any case where, by agreement Provisions, exclusive judgment over such crimes may be secured to the Local Indian tribes singly (Levy Mellor, 2008).The act to provide a temporary government for the state of Oklahoma, and the need to enlarge the law of the United States court in the Indian Nation, gave Indian courtÃ ¢Ã¢â ¬s jurisdiction over all cases. Citizens of the state by nativity or even by adoption will be the only parties. Section 31 provided that not anything in the act will be interpreted as to deny any of the judicial tribunals of enlightened states of complete authority over issues emerging in which citizens of these states by ag reement, nature or adoption are the main parties. These parties are required by law to respond to the right and supremacy to discipline the wrongdoers for defilement of the statutes implemented by their respective councils, and such statutes are not conflicting with the laws of America.There is a difficulty concerning criminality issues where the offender is considered as the only party. The other party is not given much recognition, that is, the party to whom the sovereignty in whose identity the trial is being carried. The seventh article of the treaty provide that, if a special request is made for the prerogative of the American courts, the district courts closest to Cherokee will have complete control over the cases. The homicide was not committed within the Canadian boundaries and, therefore, article seven does not apply directly but it could have an indirect effect on demonstrating an intention to treat the prosecuting attorney as the other party to the cause.In Alberty, v Un ited States it was ruled out that it was natural for a husband to investigate when he sees another man trying to get into his wifeÃ ¢Ã¢â ¬s room window at night. The law further confirmed that the husband was not allowed to retreat when attacked with a knife under such circumstance. It is required that the man uses only as much force as is considered necessary to deter the attack. It was agreed that if in a resulting confrontation the husband shoots and kills the plaintiff and then flees away, his actions of running away would not be evident of his guilt (Martin, 2010).The case of Alberty v. United States demanded the Supreme Court to reviewing capital punishments from the Western District of Arkansas. After a depth analysis about whether the civic court carefully had jurisdiction on this issue, Mr. Billings Brown, a Judge, provided his opinion for the undisputed Supreme Court had in the truthful heart of the case. On a particular night, the Defendant saw a te...
Friday, May 29, 2020
Essay Free Sample AdviceWith so many different types of essays that can be prepared for college admissions, one can easily find essay free samples that will offer students a great deal of help in the process. If a student feels as though they are not getting the type of information that they need to help them prepare for a particular type of essay or topic, it is easy to look to different examples and samples for ideas and examples that are useful. This is the first step that many students try to take when preparing for the college essay and applying for an admission to a particular school.It should be noted that every student will have a unique situation that they will face on the college level. There are some schools that do not allow any writing of essays at all. In those cases, the students will want to look for essays free samples for learning about the various options that they can look into for composing their essay and for preparing it for college.Many students will take an i nterest in the different topics that will be covered during the course of an admission essay. They will then be looking to see if there are any tips or guides that can be used to help them with this process. A review of the essay free samples will be a great place to begin this process.The question of why some schools allow more essays than others can come from different reasons. However, the main reason will come from the reason that a student's essay will not be able to get accepted. This can happen for many different reasons, and these include a writing style that is not appropriate, that the essay does not appeal to a majority of the college admissions officers, or simply a lack of a quality essay from the student.Some students may find it difficult to find essays free samples, because they are unsure of where to look. A quick Internet search should yield some good results, as most websites that specialize in this sort of information will provide lists of a few sample essays for free. Students will be surprised at how much they can learn by reading through these samples, which will show them the type of topics that can be covered as well as what mistakes to avoid.There is one type of essay that is often written that many students will want to get used to. This is the 'book report,' which consists of writing a short paper based on a book chapter. When looking for essay free samples for this type of topic, the students will find that there are plenty of essay examples for a book report available online that can be used for this purpose.When looking for essay free samples, there are several other topics that a student will need to know about. These include the different topics that will be looked at during the admissions process. Students should also be able to find ways to make their essay stand out from the others that will be offered.An essay can be a tricky subject, because it has to be written in a way that will appeal to the admissions officer and will also be able to display the proper writing style. To help with this, there are many free samples that are available online, but it will be important for students to find ones that are specifically written for use on the admissions level. After all, the goal of the essay is to show the admissions officer that the student is the best candidate for the school.
Tuesday, May 26, 2020
<h1>Choosing Cultural Analysis Essay Topics</h1><p>In request to get ready for the test, you ought to settle on your social examination paper subjects. The accompanying rundown contains a couple of tests of paper points to consider.</p><p></p><p>For numerous understudies, math is only a numbers game. That is the reason understudies are frequently abandoned by their cohorts who exceed expectations in language expressions and humanities. Because understudies do well in math doesn't mean they have excellent verbal skills.</p><p></p><p>Speaking and composing abilities can be created through legitimate investigation propensities and practice, however hardly any understudies know about how to expand their math aptitudes. While doing admirably in math may prompt high grades, it's not generally the correct procedure. Understudies ought to likewise figure out how to read for a state sanctioned test, not simply center around get ting ready for a test. This causes them to improve their capacities and set themselves up for their test in a manner that empowers further learning.</p><p></p><p>There are numerous social establishments over the present reality that emphasis on saving the past. You can increase an abundance of information about any culture by contemplating its historical backdrop. It likewise shows the understudy how their own way of life has changed after some time. When perusing, understudies must focus on what's being composed and the setting of the information.</p><p></p><p>Articles that advance assorted variety in the workforce should be composed from a viewpoint that doesn't expect everybody is the equivalent. In case you're composing an article about medical attendants, the topic ought to be adjusted for a more extensive crowd. Rather than telling it from a female medical attendant's perspective, think about a general perspective from a speciali st. You may even figure out how to make the article entertaining or contacting. So as to adequately clarify your point of view, it is critical to know the perspective of others.</p><p></p><p>Before picking exposition themes, consider all the data you have to add to your paper. In spite of the fact that finding out about some particular points may just require a short note, others may require broad research. Incorporate however much material as could reasonably be expected with the goal that it will be anything but difficult to compose about.</p><p></p><p>Cultural examination article points are an extraordinary method to give understudies a foundation in history and culture, yet the best method to learn is through direct understanding. Perusing and learning about explicit points is useful, yet accomplishing something that is comparable is far and away superior. That is the reason knowing somewhat about different societies will give a mo re profound comprehension of the world.</p><p></p><p>By expounding on social investigation exposition points, understudies will find out pretty much all parts of their general surroundings. Finding out about occasions and places in the past will permit understudies to get familiar with various societies in the present day.</p>
Sunday, May 24, 2020
Composing an Essay in SpongebobIt's anything but difficult to be doubtful when you initially find out about composing a paper in Spongebob. Why not simply record the data in a plain note pad? In any case, there are such a significant number of valid justifications to compose a paper in Spongebob.The Plot - Spongebob is extremely odd. The plot of the show spins around certain individuals who like to paint. On the off chance that you follow the show, you will likewise observe that they are continually painting a type of elastic thing. They start with the blameless yellow wipe in an aquarium. And afterward as the season goes on, they paint an assortment of things, for example, the orange wipe with the tail, the green springy thing in the sea, and even things like the freak panda.This arrangement is likewise known for the numerous odd things that happen to Spongebob. One of them is that he incidentally gets hitched. The plot and everything that happen to make it look so fun and senseless that the best way to have a fabulous time and remain new is to do some writing.The Characters - Spongebob is constantly encircled by his companions who give a valiant effort for him. He has the pleasant human accomplice, Sandy, his snail accomplice, Patrick, and Mr. Krabs, who go about as his associate and is Squidward's sidekick. These characters have various eccentricities that make them unique.They additionally are on the whole bright in their own particular manner. You can get inventive by joining hues that you like to cause to notice certain pieces of the story. The character connections are likewise unique in the story, which implies that in the event that you pick an inappropriate character, you may fall short.Reading - Spongebob is anything but difficult to peruse. The supple pages, characters, and thoughts make it simple to peruse what is going on.The Point - Writing a paper in a tough situation by any means. You simply need to concentrate on the story line. All things con sidered, this should be amusement.
Saturday, May 23, 2020
Should I Pick a Serious Topic For Narrative Essay?Should I pick a serious topic for narrative essay? It depends on what you're writing about. For some topics, like politics, business, and others, you might find it easier to just write about your personal experience instead of dipping into that subject matter.The purpose of a story is to entertain the reader. If you're simply trying to get information out of your reader, then you're not going to have much success. But if you're trying to show a particular side of yourself or of the person you're writing about, then your story might be successful. Keep in mind that there are different styles, and that not every story can use all of them.One important thing to keep in mind is that your story has to be entertaining. If it doesn't move your reader, then it's not going to be successful. Even if you're doing something to try to draw them in and make them interested, if they aren't attracted by the story, then it isn't going to work. Keep in mind that if you want to make the story engaging and interesting, you have to keep your words flowing naturally. In order to do this, you need to learn how to present yourself, your character, and your situation accurately.The first thing to keep in mind when you're deciding whether or not to pick a serious topic for narrative essay is to remember that your characters have a specific goal in mind. If you're trying to describe the character in a way that makes him or her look evil, for example, then you probably shouldn't do so. You should keep it simple and descriptive, and the characters actions and their reactions should not make the reader doubt your decision.Secondly, remember that the reason you're writing a story in the first place is to make an impression. If you're using your story to explain why you did what you did, or to show the character in a positive light, then you should keep that fact in mind. And when you write the story down, remember that the purpose of the stor y is to show the reader a particular side of themselves, and that's what you need to focus on.If, however, you're trying to convey something in a more positive light, then you can consider writing a serious topic for narrative essay. The key is to keep it interesting, but still true to the characters or situations. If you're trying to convince your reader that your character should be a hero, then you're going to have to make it about him or her.Keep in mind that the goal of a serious topic for narrative essay is to attract your reader in. If your reader is actually trying to look at the characters through your eyes, then the story should be successful. Keep in mind that your writing skills are the most important tool that you have when it comes to a successful story.If you want to make your fictional book or essay into a successful story, then you need to know your story, your characters, and your motivations. These are the things that will make your book or essay a success. It doe sn't matter what topic you choose to use, it all depends on what style and story you want to tell.
Friday, May 22, 2020
<h1>What Should Be Included In A Secondary Essay Sample?</h1><p>Secondary article tests are valuable for understudies who need to find an extraordinary line of work after graduation, however don't have the opportunity or cash to spend in taking classes for a Bachelors qualification. They can assist an understudy with preparing his auxiliary exposition while all the while taking a shot at a Master's certificate. These examples can emerge out of an assortment of sources and help an understudy to compose an optional exposition that stands out.</p><p></p><p>Medical Schools require auxiliary papers that take a gander at the understudy's scholastic and profession objectives. Auxiliary papers should be written such that appears as though it depends on investigate and clinical experience. A few instances of hotspots for optional article tests include: course readings, guides, clinical records, diaries, research, and oral introductions. The utilizatio n of references encourages an understudy to increase some significant experience.</p><p></p><p>Secondary paper tests for the most part highlight three fundamental segments: a principle collection of content, a decision, and an outline. The thought behind an auxiliary paper is to create a compact yet all around looked into content. It is best to attempt to isolate the data in the exposition into two sections, concentrating on the target and composing an outline that sums up the objective.</p><p></p><p>Several schools and colleges require the auxiliary understudies to take part in center gatherings, which is the place the understudy gets the chance to hear straightforwardly from different understudies, this makes significant data. Understudies can acquire their own inquiries and can pose to those that will in all probability be asked by different understudies. Center gatherings additionally allow the understudies to perceive what differe nt understudies are asking and this gives them a smart thought of how to structure their inquiries and what they have to avoid.</p><p></p><p>Secondary article tests are frequently utilized as a methods for discovering approaches to make an increasingly brief type of composing. Some understudies may be planning to have their papers perused as opposed to have them perused so anyone might hear. Usingsecondary articles as a methods for building up a progressively smoothed out composing style can be useful and permits an understudy to not exclusively be an increasingly complete author, yet will likewise enable them to have a superior comprehension of what is required for their specific school or college.</p><p></p><p>The next part of an auxiliary paper is to mull over the better places in the exposition where a synopsis will be composed. Numerous auxiliary articles are required to be written in a couple of areas, yet for other people, it is required to be written in three sections. A portion of the territories of exposition that have a requirement for a rundown are inquire about papers, study abilities questions, and basic reasoning papers. At the point when the understudy utilizes this sort of paper as a methods for making a rational outline of what they have stated, they will realize the rundown that will be required.</p><p></p><p>An significant piece of any auxiliary article is to write such that makes them stand apart from the group. A few understudies may locate this troublesome, particularly on the off chance that they have been presented to a similar composing style the entirety of their lives. By figuring out how to make an increasingly unique and extraordinary exposition, and how to make it a progressively fruitful one, understudies will have the option to use these auxiliary article tests furthering their potential benefit. Hearing their point of view to an editorial manager so as to be utilized in a school or school paper isn't just simple however can be tedious as well.</p><p></p><p>There are bunches of clinical schools that require optional expositions to be written in a particular arrangement. Now and then this organization will be explicit to the kind of school and different occasions it will be the sort of paper. The most ideal approach to ensure that the papers that the understudy is composing have the best possible arrangement is to set aside the effort to audit them over again until they look right.</p>
Wednesday, May 20, 2020
<h1>Efficient Environmental Science Research Paper Topics For First Time Researchers</h1><p>One of the normal mix-up individuals make while setting up their primary paper theme is to avoid a stage and do their necessities without any preparation. This can be one of the most hazardous mix-ups in doing an exploration paper since you may wind up passing up genuinely necessary data. In such manner, here are some useful hints to get your necessary data. It would be ideal if you read this article.</p><p></p><p>o Study Questions. At the point when you have picked your topic for your exploration paper, the time has come to consider your investigation questions. Having explicit inquiries is perhaps the most ideal methods of deciding if you have enough data to effectively finish the research.</p><p></p><p>o Study Resources. At the point when you intend to have your examination paper subjects done in a homeroom, you should have a framework to get to the proper asset. Since you will be utilizing your own assets, it is fitting that you set up an agenda before you start.</p><p></p><p>o General Answers. Here you should attempt to give an outline of all the relevant focuses to ensure that you won't have any superfluous discussions.</p><p></p><p>o Text Summary. At the point when you have chosen which zones of your examination you are going to concentrate on, you have to compose a concise outline of the considerable number of subjects. Ensure that you don't get excessively energized and have any false impressions among yourself and your teacher as the educator has the last word.</p><p></p><p>o PDF. As you are making an exploration paper for your significant undertaking, you should send it by means of pdf.</p><p></p><p>With these simple advances, you ought to have the option to set up your examination paper subjects to g uarantee that you are putting the most effective and right measure of data to finish the venture. If it's not too much trouble consistently recall that you are attempting to take care of an issue; consequently, your exploration papers ought not be too difficult.</p>
Saturday, May 16, 2020
S-Adenosyl-Methionine (SAMe) And Improved Methylation Offer A Serious Alternative To Orthodox Medications - Health Dissertations - Free Essay Example
Sample details Pages: 32 Words: 9620 Downloads: 8 Date added: 2017/06/26 Category Health Essay Type Research paper Did you like this example? S-Adenosyl-Methionine (SAMe) And Improved Methylation Offer A Serious Alternative To Orthodox Medications Can S-Adenosyl-Methionine (SAMe) and improved methylation offer a serious alternative to orthodox medications in the treatment of depression? Abstract In this dissertation we consider the issues surrounding the use of SAMe as an antidepressant. There are many different aspects to this consideration. We start by a consideration of exactly what depression is on a clinical basis and examine the psychological and physiological changes that characterise the condition. We then consider and examine the evolution of the current forms of antidepressant medication. We explore the fields of neurochemistry and pathophysiology of depressive states with particular emphasis on the chemistry of the methylation reaction and its relevance to the SAMe compound. Consideration is then given to SAMe specifically as a medication and the evidence that there is to support its apparent beneficial effect in depression. This is then expanded with a review of the chemistry of SAMe and its intera ctions with other biologically active entities. We conclude the exploration with a critical review of the published literature that is relevant to the role of SAMe as an antidepressant agent. Introduction In order to investigate the full extent of the question at the heart of this dissertation we must examine a number of background issues in some detail first. Depression is a complex clinical state. It has been said that there are as many theories about the aetiology and treatments for depression as there are clinicians thinking about the problem. (LeDoux, J. 1996). A brief examination of the literature on the subject tells us that this comment, although clearly intended to be flippant, may not actually be so very far from the truth. Perhaps it is because of the plethora of hypotheses, ideas and theories on the issue that there are also a considerable number of forms of treatment that are commonly employed. It has to be admitted that some are rational and some appear to be completely irrational. In this dissertation we shall examine some of the more rational forms of psychopharmacology in order to understand the place of SAMe in the therapeutic pharmacopoeia. Depression is a commonly occurring illness. It will significantly affect between 10-25% of women and approximately half that number of men during their lifetimes. Approximately 5 million people in the UK will experience significant depression in any given year. (Breggin 1994) If you suffer from an acute or chronic illness you are even more likely to suffer from depressive states with frequencies ranging from 30-50% depending upon the nature and severity of the illness. (Robertson et al 1997) What is depression ? There are many definitions of clinical depression and indeed many different rating scales which purport to try to quantify it. It is important to distinguish between clinical depression and simply feeling down or miserable. Depressive illness typically occurs in episodes al though in some cases it can actually last for many months or even years. (Skolnick, P. 1999). One severe depressive episode is a major independent risk factor for getting further episodes. In other words, having had depression once you are statistically considerably more likely to have another attack. (Post RM. 1992). For our purposes we shall consider a practical overview of the nine classic symptoms that characterise classical depression 1. Depressed mood for most of the day 2. Disturbed appetite or change in weight 3. Disturbed sleep 4. Psychomotor retardation or agitation 5. Loss of interest in previously pleasurable activities; inability to enjoy usual hobbies or activities 6. Fatigue or loss of energy 7. Feelings of worthlessness; excessive and/or inappropriate guilt 8. Difficulty in concentrating or thinking clearly 9. Morbid or suicidal thoughts or actions. (After Zuess 2003) The Diagnostic and Statistical Manual of Mental Disorders (DSM-I V) states that in order to merit a diagnosis of clinical depression you need to demonstrate at least five of these symptoms and that they represent a change in your life. Mood alterations are commonplace in depressive states. The depressed patient will classically feel despair or sadness. Pleasure becomes an alien emotion as they tend to progressively loose interest in activities that they would have previously enjoyed. Mood swings can also occur although they are more commonly found in bipolar states (manic depression). Subjective feelings of tension or irritability are often described as well as just sadness. (Duman et al 1997) In addition to mood changes, depression can also produce changes in the emotional state as well. Feelings of worthlessness and guilt are perhaps the commonest emotions in the clinical spectrum. This is closely followed by both ineptitude and lack of confidence in ones own abilities or capabilities. It is common for depressed people to take action that avoids them having to take responsibility because of an overwhelming fear of failure. (Altar CA 1999) Somatic manifestations of depression are perhaps easier to quantify as they have a qualitative characteristic about them as opposed to the purely subjective. Changes in appetite are commonly found. Generally it is an anorexic change with a decrease in appetite and a loss of interest in food generally. Less frequently, the converse is observed with a voracious increase in appetite (comfort eating) which is normally associated with weight gain. This weight gain can be quite substantial in extreme cases. Sleep disturbances are commonplace. Insomnia and early waking are perhaps the commonest of this type of symptom. This can occur despite severe subjective symptoms of somatic tiredness and fatigue. Some people will find that fatigue is a prominent symptom and may find that this is translated into excessive sleeping and motor retardation generally. Fatigue is actually more diff icult to quantify, but it is commonly experienced by the depressed patient. It can either be an overwhelming tiredness (lack of energy) or perhaps lack of stamina (tiring too easily). Associated with this is often a reduction in libido and, if severe, impotence can also occur. It is not unusual to find sexual avoidance behaviours developing in these circumstances. (Janicak et al 1989) Concentration is commonly impaired. Generally speaking the greater the degree of depression, the greater is the degree of concentration impairment. Thinking and reasoning processes slow down and the attention span is often markedly reduced. Students find they can have an inability to study and if severe, patients report an inability to even sit and watch television. (Bazin et al 1994) Somatic symptoms can occur without the psychological elements of the depression being apparent or obvious. This is a common clinical dilemma. Patients may enter a phase of denial or minimisation where they will not accept that they are actually depressed. They can try to rationalise their physical symptomatology into other disease processes. This can be mistaken for hypochondriasis. (De Vanna et al 1992) If depression is severe (or occasionally part of a symptom complex of another underlying pathology), then psychosis can be found. Delusional states are not uncommon in severe depression. Hallucinations can occur, but they are comparatively unusual. Patients can state that they hear voices telling them that they are worthless or perhaps instructing them to kill themselves. Although this is consistent with a depressive diagnosis, one should note that other illnesses such as schizophrenia must clearly be considered and excluded before a confident diagnosis of depression can be made. The actual basis or specific triggering factors for depression are not yet clearly defined but we do know that a number of different biological factors are relevant. Environmental factors, together with both gen etic and neurobiological elements are all capable of influencing the overall clinical picture. (Kendler KS, 1998). Depression is broadly divided into endogenous and reactive types. In general terms endogenous depression is thought to be influenced the genetic and neurobiological factors whereas reactive depression may well have environmental factors as being relevant. This has considerable implications in our considerations of the possible actions of SAMe. (Gold et al 1988) Pharmacology of depression This is a vast subject and is generally considered to be a sub-speciality in its own right. It has long been recognised that certain substances appear to be able to exert a mood elevating effect. The advent of modern psychopharmacology allowed us to develop an understanding into just how some of these substances work. The drugs and medicines that are in common use today are the result of a process of evolution that, arguably, began with the uses of herbs at the beginning of rec orded history and progressed to the chemically and biologically sophisticated compounds that are in use today. (Peinell and Smith 2003) In order to put the SAMe compounds into their appropriate place in the continuum we need to look at some of the evolutionary developments in the field. Most of the currently used antidepressants work by interfering in some way with the actions of the various neurotransmitters in the brain. Many work by slowing down the biological processes of degradation or destruction of these neurotransmitters. In purely simplistic terms, this results in a greater concentration of the neurotransmitter at the critical synaptic interfaces within the brain. (Levine et al 1998) The first real breakthrough with what could be considered to be a major therapeutic agent for depressive states came with the discovery of the MAOI (Monoamine Oxidse Inhibitors), group of drugs. Three were commonly used in clinical practice isocarboxazid, phemelzine and tranlcypromine . For a while they were used extensively but it became obvious that they had serious drawbacks including some potentially fatal side effects. (Saarelainen et al 2003), Headaches dizziness and tremor were not unusual accompaniments of the drug. They also had the ability to interact with other medications and certain types of food (tyrosine containing foods such as cheese could cause hypertensive crises). Despite these drawbacks, many patients were willing to take them because they indisputably worked. (Skolnick 1999) In time, the MAOis were superseded by the Tricyclic group of drugs. There were four in common use, namely amitriptyline, desipramine, imipramine and nortriptyline. These were generally speaking, marginally more effective than the MAOIs but they were without the worst of the side effects. Despite that, they were still able to cause dry mouth and blurred vision in some people. Constipation and drowsiness were not unusual and they were not commonly used if a person al so had hypertension. The pharmaceutical industry then produced a number of different categories of medication in fairly quick succession. SSRIs (Selective Serotonin Reuptake Inhibitors), SNRIs (Serotonin and norepinephrine reuptake inhibitors) and NDRIs (Norepinephrine and dopamine reuptake inhibitors) all emerged into the market place. (Smith et al 2004) It is probably fair to say that they all had their niches in the therapeutic spectrum but the SSRIs were seen to corner the biggest share of the clinical market with citalopram, escitalopram, fluoxetine, paroxetine and sertraline as examples of the group. Fluoxetine was probably the most widely used and its trade name, Prozac was accepted almost as a household word. The side effect profile of this particular group was certainly less significant than their predecessors, but nausea and headaches were not uncommon. (Stewart et al 2000), The SNRIs fell into disuse largely because of their reputation in raising cholesterol l evels and the NDRIs were found to cause unacceptable agitation in certain groups. There was then an emergence of a group of drugs which not only blocked the mechanisms that removed the trophic neurotransmitters from the synapse they also had an effect which effectively enhanced their action by blocking the action of the inhibitory neurotransmitters at the same time. There are several types of medication in this category, but perhaps the best known is maprotilene. Like most of the other types of effective medication, it is not without side effects. Drowsiness, nausea, dizziness and a dry mouth are common accompanying symptoms of a therapeutic dose of this medication. (Harmer et al 2003) Neurochemistry and pathophysiology of depression So far we have take a brief and admittedly comparatively simplistic tour of the nature and pharmacology of depression. We shall now look at the neurochemistry and pathophysiology of certain relevant aspects of the subject in more detail. In general terms, stress and antidepressants appear to have reciprocal actions on neuronal growth and to some extent, on their activity (see on). This appears to be through the mediation of various neurotrophins and the action of synaptic plasticity mainly in the region of the hippocampus and some other brain structures (Reid et al 2001). Various stresses appear to disturb and disrupt the activity, both of individual neurones and also larger functional groups, or networks of neurones whereas antidepressants appear to antagonise this disruptive ability. (Henke 1990) There is a large body of opinion which agrees with the hypothesis that regulation of synaptic activity is a major key to the pathophysiology of depression and related disorders. (Drevets et al 1997) The discovery of the MAOI group of drugs (above) led researchers to speculate that the monoamine group of neurotransmitters were central to the aetiology of depression. As more research is done it is becoming apparent that this may not actually be the case. It is now considered more likely that the fundamental problems lie further along the metabolic cascade from the monoamine oxidase activity. It is also considered likely that the pathology may well not be just a chemical imbalance, but may well involve other functions of neural tissue such as various cellular changes in physiology, genetic factors and the ability of neuronal network to change their characteristics. (Czyrak et al 1992) Observational studies have suggested that early life experiences, the impact of stress and the presence or absence of social support or interactions all have an influence on the development of a depressive state. (Gould et al 1998).Consideration of the monoamine chemistry clearly does not account for all of these factors although it is clearly acknowledged that it does play an important contributory role. Some recent work relating to the chronic use of different classes of antidepressants (Duman et al 1997), has appeared to show that they all are able to increase the production of the neuroprotective groups of proteins which, amongst other actions, play a central role in the plasticity of neurones. Current thinking is that this may well be a common function of a number of different pathways that the different antidepressants exploit. It is known that increases in monoamine levels in the synaptic region result (by a number of different mechanisms) and are associated with the induction of enzyme systems that control gene expression within the neurone. This can be inferred from the finding of increases in the levels of messenger RNA which codes for the cAMP response element binding protein (CREB). These levels slowly increase with chronicity of administration of antidepressants and this mechanism may well account therefore for the commonly observed slow and progressive onset of action of most of the antidepressant drugs. It is proposed that CREB triggers the production of BDNF (Brain Der ived Neurotrophic Factor). This is significant since other work has shown that stress antagonises the levels of BDNF which is opposed by the actions of the antidepressant drugs. (Smith et al 1995). Further credence is given to this theory with the discovery that placing BDNF directly into the brain of experimental animals appeared to relieve many of the behaviour patterns that are associated with depression (Siuciak et al 1997) Some authors have suggested that depression may represent a particularly subtle form of neural degenerative disorder as it has been shown that the hippocampus becomes progressively atrophic in chronic depressive states. This is particularly significant as BDNF is thought to reverse such findings. (Shah et al 1998). There is associated supporting evidence in the form of a study by Vaidya (et al 1999) which shows that ECT treatment (which was always assumed to be detrimental to the neural structure and physiology) is associated with both increased levels of BDNF and trophic changes in the hippocampal neurones. A paper by Czyrak (et al 1992) looked at the antidepressant activity of SAMe in mice and rats in a way that clearly is not possible in humans. It is not always possible to directly extrapolate findings from animals to humans, but there are some pieces of evidence in this work which strongly implicate SAMe in the pathogenesis of depression. The paper itself is extremely long and complex but the relevant parts to our considerations here are the fact that normal geographical exploratory behaviour in rodents tends to diminish if a depressive state is induced. To some extent, exploratory behaviour is therefore considered a marker for the depressive state. It was found that SAMe tended to increase exploratory activity in mice. This, and other more sophisticated testing of the pharmacological interactions of SAMe showed that it tended to have the same psychopharmacological profile as many of the mainstream antidepressants. Man y of the neurotransmitters and for that matter some neuroactive hormones have been variously implicated in the aetiology of depression (eg thyroid hormones and noradrenaline). (Nemeroff, 1998). Modern research has most consistently found that alterations in the levels of serotonin (5-HT) (Melzter H, 1989), system and the chemicals of the Limbic Hypothalamic-Pituitary-Adrenal (LHPA) axis. (Kathol et al 1989), as the most consistently implicated mechanisms that appear to be associated with the control of the mood stabilising and regulating mechanisms. It is in fact very likely that both these mechanisms are in some way interlinked as part of the regulatory mechanism of mood. We have already referred to the role of stress in the aetiology of depression. We know that the adrenal glucocorticoid hormones subtly interact with the 5-HT system and these are produced in direct response to stress. (Lopez et al 1999) (I). We also know that the glucocorticoids have a number of direct effects on the Limbic Hypothalamic-Pituitary-Adrenal (LHPA) axis. It may be that this is the mechanism by which stress antagonises the changes brought about by SAMe. (Lopez et al 1999) (II) We do not need to consider the effects of the corticoids on the LHPA axis in detail as it is only of peripheral relevance to our considerations here. The important consideration in this regard is that the LHPA axis is intimately connected to the hippocampus. It is this structure that is the intermediate step and connection between the bodys hormonal response to stress and the response of the higher functions of the brain. (Dallman et al 1987). The immediate relevance of all this to the actions of SAMe are that hyperactivity of both the hippocampus and the LHPA axis are both well documented in cases of clinical depression. This has been shown to also be associated with high levels of corticosteroid production (Kalin et al 1987), but one study has shown that in suicide cases who have had profound dep ression the hippocampus has fewer corticosteroid receptor sites than one might normally expect (Lopez et al 1998). One further piece of clinical evidence in the role of the corticosteroids in depression is that patients with Cushings disease have a high incidence of depression. This incidence returns to normal when their hormonal over-activity is treated and returned back to physiological levels. (Murphy 1991) SAMe as a medication SAMe was discovered in Italy in 1952 during research into the chemistry of neurotransmitters. It was not, however, introduced in a useable form for patient benefit until 1974 (as SAMe sulphate-paratoluene-sulphonate). It is for this reason that the majority of the early papers and work on the subject are almost exclusively Italian in origin. (De Vanna et al 1992) SAMe has been used clinically in a number of conditions including cholestasis, osteoarthritis and depression. (Carney et al 1987) Although there is a wealth of literature on the first two elements it is not relevant to our considerations here. We shall therefore restrict this discussion to the spectrum of its use in the field of depression. A number of studies have shown that SAMe has useful activity in depressive illness. Studies that have compared it to placebo have found that it can consistently produce about a 6 point increase on the Hamilton rating scale after about three weeks of optimum treatment. This finding is approximately in line with the results that are found with most of the other clinically effective antidepressant medications. (Cooper et al 1999) (De Vanna et al 1992) Some studies have found that using SAMe in a large dose has produced an unusually rapid onset of beneficial effects (Kagan 1990) One could argue that, because it is a naturally occurring substance, it would not be likely to have a high side-effect profile. Although these two statements do not always follow, it is generally true. A study by Bressa (1994) on the issue showed that it did have a particularly low side-effect profile, particularly when compared to the other antidepressants (Tricyclics). To demonstrate this point further, we can point to the study by Caruso (et al 1987) where there were a greater number of patient withdrawals due to the side effects of the placebo than withdrew because of the SAMe drug. For the record, that particular trial was in its use as an antiarthritic rather than an antidepressant, but the point is made. The two major unwanted clinical effects are nausea and hypomania. The nausea is not a local effect on the gut lining but appears to be a centrally mediated effect and is possibly caused by the same phenomenon of over-stimulation of the neuronal networks which causes the other major clinical manifestation of hypomania. For this reason it is generally not used in cases of bipolar disorder. (De Vanna et al 1992) It is probably not strictly accurate to refer to SAMe as a drug as it is normally found in the cellular matrix. It has been found to be effective in patients who have been unable to tolerate other forms of antidepressants or, for that matter, have had minimal response to them. (Reynolds et al, 1984) Young (1993) produced a particularly interesting review of dietary treatments for depression. A lot of his article is not relevant to our considerations here, but he makes a number of interesting and relevant observations. Low serotonin levels are known to be associated with depression even though low levels on their own do not appear to cause the condition. It appears that it needs to be in combination with a low level of folic acid. We know that low levels of folic acid are also often found in combination with depressive illness and that low levels of folate are often associated with low levels of SAMe. The evidence points to the fact that the low levels of serotonin are more likely to be a result of the low SAMe levels in neural tissue and that this is more likely to be nearer to the root of the main anomaly that causes depression. Pregnancy is known to be associated with low levels of folate and post natal depression is a well recognised clinical entity. Salmaggi (et al 1993) considered the effects of SAMe in the postnatal period. This was a well considered and constructed study. It was a double blind placebo controlled trial over a 30 day period and had an entry cohort of 80 women. The degree of depression was assessed before, during and after the trial on the Hamilton Scale. The results showed a statistically significant improvement in the SAMe group when compared to the placebo group. The authors comment that there were no significant side effects of the medication encountered. Because we know that any beneficial effect that SAMe is likely to have on a patient tends to be seen more quickly than with the other antidepressants, and also, by virtue of what we suspect about its probable mode of action in the hippocampus and elsewhere in the brain, i t seems a logical step for someone to look into the effects of giving SAMe alongside a conventional antidepressants to see if there is either any synergistic effect or possibly a speeding up of the clinical onset of the secondary medication. The study by Berlanga (et al 1992) did exactly that. Unfortunately the trial was not particularly rigorous in its design as although it was double blind, it was not placebo controlled, which would appear to have been the method of choice in this type of investigation. Its other problem as that it only had an entry cohort of 40 patients. Despite these limitations it was indeed shown that depressed patients who took SAMe in conjunction with other antidepressant medication found that the depressive symptoms resolved faster with the SAMe added to their normal treatment regime. There are one or two other less important papers which we shall only mention in passing. Kagan (et al 1990) ran a small trial on 15 inpatients (with very severe depressi on) and found SAMe to be a safe, effective antidepressant with few side effects and a rapid onset of action. This particular trial is notable as it was the first to report the side effect of mania in a patient who didnt have a previous history. Another is the trial by Rosenbaum (et al 1990). This particular trial is notable for the demonstration of the fact that about 20% of other treatment resistant patients experienced benefit with SAMe. Faya (et al 1990) (II) considered the fact that SAMe is thought to exert its effect through its action in increasing dopamine levels in the synaptic cleft. It is known that dopamine inhibits the production of both Thyroid stimulating hormone (TSH) and Prolactin from the pituitary gland. Faya considered measuring the levels of both TSH and Prolactin during treatment with SAMe. His findings constituted something of a surprise insofar as in the men in the trial group had their levels of TSH and Prolactin reduced which is consistent with the hyp othesis that SAMe increases the dopamine levels in the brain. Much to everybodys surprise, this effect was not seen in the female group. The authors do not offer any explanation of this fact. For the record, there is another trial (Thomas et al 1987), which obviously considered the same phenomenon and their trial did not show any sex linked difference in the suppression of the Prolactin levels With regards to efficacy, a trial by Carney (et al 1986) suggests that the beneficial action of SAMe is restricted to endogenous depression and it does not appear to have any action above placebo on reactive depression. As far as we can ascertain, this is the only trial published that has made this suggestion, although from a first principles basis, one can see the biochemical rationale for believing that it might well be the case. On a purely empirical grounds, some authors have recommended (on the basis of scant hard evidence), that SAMes action can be maximised by the addition of B 12, B6 and folic acid. It is known that SAMe is required to convert these agents into their active form as a coenzyme. (Morrison et al, 1996). The same author also recommends the simultaneous adminstration of Trimethylglycine (TMG) which is necessary for the intracellular conversion of methionine into SAMe by the provision of the necessary methyl- groups. Comment has to be made that again, this appears to be a completely empirical (and logical) suggestion, but we cannot find any hard evidence to substantiate its clinical use. Chemistry SAMe is a basic component of cellular biochemistry. It occurs in every living cell and is second in importance only to ATP in both the number variety and significance of the reactions in which it serves as a cofactor. (Stramentinoli 1987). It is central in the chemistry of the transmethylation reactions. In essence its cellular function is to transfer the active methyl group form carrier molecules to a multitude of other molecules. In general terms, this methylation makes inert molecules biologically active. In addition to the transmethylation reactions it also plays a central role in transsulfuration and aminopropylation reactions It is involved in the synthesis of proteins including the nucleic acids, fatty acids, lipids and phospholipids, porphyrins and polysaccharides. In terms of our considerations here, perhaps the most significant reaction type that SAMe is involved in is the generation of the neurotransmitter amines. In this regard it is considered to be the most biologically significant provider of methyl groups within the cell. (Baldessarini 1987). Significantly it is also involved in the pathways to produce a number of other neurologically active compounds such as adrenaline, the neuronutrients acetyl l-carnitine and phosphatidyl choline (Mathews et al 1990) It is also to be found in the metabolic pathways of both serotonin and dopamine. Oral administration has been shown to increase the metabolites of these compounds in the CSF (implying increased turnover). It is thought to exert its antidepressive effect partly through the mechanism of increasing the levels of both dopamine and serotonin as neurotransmitters, but it also appears to have some form of trophic action on some of the neurones in the brain cortex. (Baldessarini 1987) It has been demonstrated that the tissue levels of SAMe tend to diminish with age and blood levels are also found to be low in some cases of clinical depression (Baldessarini 1987) A methyl group (CH3) is a group of three hydrogen atoms bound to one carbon atom. It does not exist in a stable isolated form and is transported between molecules by intermediaries such as SAMe. Methylation is the process by which this group is transferred from the methyl donor molecule to the recipient molecule. In general terms this process is central to the control of many of the intracellular pathways. Giving a methyl group to an enzyme is often the key to a ctivating it, and thereby beginning a synthesis or degradation process elsewhere in the cell. Equally removing the methyl group will render the enzyme inactive and stop that particular pathway. Similar mechanisms are involved in the expression of genes and therefore the production of proteins within the cell. Some specific methylation reactions include the methylation of phenols which detoxify them and thereby aid in their excretion. (Stramentinoli 1987) In the context of this dissertation, methylation is also central to the metabolic chemistry of serotonin (and therefore also melatonin). The activity of both these compounds is effectively regulated by the presence of a methyl group. SAMe is synthesised from methionine, a naturally occurring amino acid. As the name implies (METH-ionine), it contains a methyl group. By utilising the energy supplied by ATP and in the presence of magnesium, it is converted into SAMe. The process is catalysed by the intervention of the enzyme M AT (methionine adenosyl transferase) (Bigger et al 1990) As we have discussed, SAMe is a methyl donor. When it has donated its methyl group to the recipient molecule it becomes homocysteine. The cycle is completed when homocysteine (which is a methyl sink or potential recipient) accepts back a methyl group to become methionine once again. The relevance of this association of SAMe with homocysteine is of great importance, as homocysteine has recently become recognised as a source of major morbidity. High levels of homocysteine are associated with cardiovascular disease, hypertension and a number of degenerative illnesses. It is thought to be associated with a high incidence of spina bifida and a number of other neurologically based birth defects. High levels of homocysteine have been found in some cases of severe depression It is at this point that the significance of the relevance of folate and B12 becomes clear. It is one of the biochemical pathways that can supply methyl groups to homocysteine, thus detoxifying it. There are other potential pathways involving choline and other molecules but it is thought that the B12 and Folate pathways are the most clinically significant. Another way that homocysteine can be remethylated is through the mediation of B6 and magnesium. This allows the homocysteine to be converted back to the clinically safe cysteine. It may well be relevant, but we cannot find any work to support it directly, that methylation is also vital in the removal of many of the heavy trace metals that find their way into the body. This may well be relevant to our considerations here because it is well known that many of the heavy metal group are potent neurotoxins and neuroinhibitors. It is not surprising that such a centrally important molecule as SAMe is affected by a number of other clinically important molecules. B2, B6, B12 and folic acid deficiencies will all impair the ability of SAMe to be produced in sufficient quantities for optim um action. Equally it follows that SAMe is required to convert both folic acid and B12 to their active co-enzyme forms cyanocobalamin and methylcobalamin, both of which are important in maintaining the structural integrity of the myelin sheaths of the peripheral nerves and the membranes of the CNS neurones. We have discussed traumatic experience evidence for SAMe increasing the action of some of the neurotransmitters (specifically Noradrenaline, serotonin and dopamine). It appears to do this by improving or facilitating the binding mechanisms between these entities and the cell receptor sites. (Cohen et al 1989) It also appears to have a direct action on the neural cell membrane. Functionally it is not clear exactly what this action is, but structurally it increases the synthesis of a major structural ingredient of the membrane (phosphatidylcholine). By means of its ability to methylate enzymes, it is able to influence the production of polyamines which are vital in the pro cesses of phosphorylation of proteins within the CNS neurones. This appears to be a mechanism which is central to the mode of action of many of the more conventional categories of antidepressants. Brain tissue is unique amongst the tissues of the body in that it runs at 100% metabolic activity 100% of the time. Mitochondrial function is therefore vital to the integrity and continued proper function of the neurones. SAMe is necessary to maintain mitochondrial activity. It is theoretically possible that there is another pathway by which SAMe can influence depressive symptomatology. (Evans et al 1998) One other strand of evidence comes from the fact that the methylation process is important in the production of many of the anti-oxidants which are now realised to be vital in the protection of neural tissues. Specifically SAMe is vital to the production of glutathione which is a strong antioxidant and normally found in high concentrations in neural tissue. (De La Cruz et al 1992) Following our discussions so far we have to consider the issue of why is the process of methylation so important biologically? We have already examined the processes of pathway control by methylating (or activating) rate limiting enzymes. And we have mentioned the role of DNA and RNA in protein production. The process by which genes are switched on and off is, in part, a process of methylation. There is a genetic component in depression and therefore this becomes a relevant consideration (Janicak et al 1989) The methylation of cytosine is comparatively easily measured in biological samples and as such, it represents a marker for the methylation status of the body. At birth, a child has cytosine methylation rates of between 2-6% (range depends upon the particular type of cell measured). This is a reflection of the level of activity of the genes in the DNA which are currently active. In numerical terms the nuclear portion of the cells DNA would have about 90 million methyl gro ups. (Smith et al 1998). As life progresses, the reduction of the measurable levels of methylated cytosine is a measure of the ageing process. The cellular controls and the ability to access genetic information reduce as the methylation levels drop. Certain cancers seem to develop once the methylation level drops below about 80% of maximal methylation and auto immune diseases also appear to have a correlation with this level. It is postulated that depression might also be a part of this spectrum. For the record degeneration reaches a point which is incompatible with life once about 40% of the methyl groups in cellular DNA are lost Studies relating to SAMe efficacy as an antidepressant. Literature Review As we have commented above. SAMe became available for use on prescription in 1974. Since then a number of trials (of variable quality) have looked at its indices of action. One of the major clinical features of SAMe is the unusual speed of onset of action when it is co mpared to other antidepressants. For reasons that we have explored above, most of the other antidepressants would not be expected to exert any significant beneficial effect until about two or three weeks after beginning the course at a therapeutic dose. Faya (et al 1995) looked at enhancing the speed of onset of action by using SAMe parentally. The trial design was neither blinded nor controlled as it was a simple study of 195 patients receiving the drug by this method. The authors observed that a measurable response was found to the extent that the symptoms remitted between 7 and 15 days. This particular trial is not very satisfactory, not only for the reasons of trial design mentioned above, but also because the authors do not tell us how they measured the degree of resolution of the symptoms. They did however, comment on the fact that even when giving the patients a comparatively large dose (400mg IM) they found no evidence of serious adverse effects. One way to avoid the s hortcomings of small cohorts in a trial is to perform a meta-analysis of a number of trials. Bressa (1994) provided us with the most recent reliable work in this respect. He conducted a meta-analysis of all of the major double blind placebo controlled trials that had been published up to that date. One of the problems that he experienced was that different trials defined their particular endpoint in different ways. For that reason he gives the overall response rate as between 17 and 38% (when compared to placebo results), and the degree of the response is comparable to that of the tricyclic group of antidepressants. Bottiglieri (et al 1994) (I) produced a paper which gave an overview of the currently known activity and significance of SAMe in the neuropsychiatric disorders. It covers much of the same ground that we have already explored above but it is significant in that it refers to evidence that deficiencies of both Vit B12 (cyanocobalamin) and folate have been found to be ass ociated with reductions in the concentrations of SAMe in the CSF. Sadly he does not give any references to where he found this information so we cannot check its credentials. He does, however, draw attention to the fact that it is well known that deficiencies of both cyanocobalamin and folate are associated with a number of other neurological manifestations, namely depression myelopathy, a number of forms of dementia and peripheral neuropathy. He comments on the fact that it is unlikely to be a coincidence that the metabolic pathways of these substances are intimately related to those of SAMe and that SAMe is demonstrated to be of clinical value in depression and some forms of dementia insofar as it can improve their cognitive function. It equally follows that the same statement is true when you consider the fact that treatment with methyl group donors (such as SAMe ) are found to be beneficial in treating the demyelination effects of the inborn errors of metabolism that involve both the folate and C-1 pathways. In contrast to the Faya study mentioned above, the study by Bell (et al 1994) was fastidious in both its design and execution. It was a double blind randomised medication comparison (desipramine) trial with clearly defined entry and exit points. It chose to compare the relationship between plasma levels of SAMe and the clinical response that was found in patients who had a major depressive illness. The only significant criticism that one could reasonably level at this particular trial structure was that it had a small entry cohort of only 26 patients. Given the fact that each required a huge amount of input it is not really surprising that there were not many, but the fact of the matter is that it is difficult to get statistically significant results from such a small cohort. The results were really both impressive and significant. In terms of clinical response. In terms of clinical response the authors found that at the end of the 4 week tria l 62% of the SAMe treated patients had significantly improved. The definition of improvement was given as a 50% decrease on the Hamilton Depression Rating Scale (HAM-D). This compares with the 50% improvement found with the desipramine group. So in this respect, SAMe compared favourably with desipramine. The really significant finding from this trial, at least in the context of this dissertation, was the fact that regardless of which medication the patients were given (either SAMe or desipramine), the ones that did respond were found to have a significant increase in the blood levels of SAMe. This is very good evidence that there is a direct correlation between the degree of improvement of severely depressed patients and the blood levels of SAMe, irrespective of the treatment type. This strongly suggests that SAMe has a major role in the determination and control of mood. This is possibly one of the strongest pieces of evidence that we have found, in terms of hard demonstrable fa ct, that SAMe does have a place in the treatment of depressive states. This finding is expanded further by Bottiglieri (1994) (II) who writes another review of the current knowledge relating to SAMe. In this review he takes a slightly different, neurological perspective. He points to evidence which shows that although there is no consistent evidence to link SAMe with psychiatric illness, low levels of SAMe in the CSF have been found in patients with other neurological deficits such as Alzheimers Disease, subacute combined degeneration of the spinal cord (SACD) and some of the HIV associated neuropathies. Other studies have also been able to demonstrate the finding that SAMe levels are low in patients who have suffered depression. (Johnstone Stevens 1992). The same study also found that the enzyme MAT (which catalyses the reaction between methionine and ATP to produce SAMe) was found to be low when assays were done on the red blood cells of depressed patients. Further evide nce comes from the paper by Baldessarini (1987) in which the authors found that SAMe has low levels in dementia alcohol abuse and increasing age. This point may well be relevant insofar as it is well known that patients who are depressed are more likely to use alcohol as a means of mediating their symptoms. The fact is that this actually worsens their overall condition. An excess of alcohol interferes with the production of SAMe. The situation is compounded by the fact that SAMe is required in the liver to provide the methyl groups necessary for the methylisation and detoxification of alcohol. In short, alcohol reduces the levels of SAMe which are therefore not available to detoxify the alcohol. This can result in liver damage. The lowering of the SAMe levels increases the tendency to clinical depression and therefore the patient will often feel the need to drink more, and so the cycle continues.. (Reid Reynolds 1994). This is really a very well written, researched and complex p aper which we have, (for obvious reasons), extracted the relevant pieces of information that are strictly relevant to this dissertation. In the paper by Flynn (et al 1994) it has is reported that giving SAMe supplements to these patients not only appears to protect the liver against the toxic effects of alcohol, but it also can reduce alcohol-related depression. (Kegan et al 1990) Trials have also been done in the depressive states that can frequently accompany Alzheimers Disease. In this condition, SAMe blood levels can be very low to the point where they can be almost undetectable. (Smythe 1998) Morrison ( et al 1996) found that SAMe can produce small, but measurable, improvements in the depressive score ratings of some patients with Alzheimers Disease . In terms of efficacy, there is plenty of evidence to show that SAMe is superior to placebo, but few well constructed trials have sought to demonstrate that it is actually as good as, or perhaps superior to conventional medications. (Rudoref et al 1989) compared SAMe to a number of other antidepressants currently in use at the time. His results show that SAMe was at least equal to, and in some instances superior, to imipramine (a tricyclic antidepressant). This particular paper reports the results of a number of smaller separate trials, all of similar design. It has to be said that the entry cohort for each were actually very small and therefore proper statistical significance cannot really be applied to these reported findings. (Kegan et al 1990) found that patients who did not respond well to mainline antidepressants or alternatively had unacceptable side effects, could have a good response with SAMe. Again, the numbers involved were comparatively small. Conclusions and Discussion Throughout the dissertation we have been endeavouring to answer the question Can S-Adenosyl-Methionine (SAMe) and improved methylation offer a serious alternative to orthodox medications in the treatmen t of depression? From the evidence that we have assembled it would appear that the answer is a qualified Yes. There is little doubt that examination of the evidence that we have for the neuroactivity of SAMe suggests that it is certainly a good candidate for influencing the neural pathways that control and regulate mood. From both a theoretical and a practical perspective we can see that it probably SHOULD work. As with most things in the field of pharmaceuticals, there is a huge gulf of difference between thinking that something should work, and the reality of it producing good, consistent and safe results in the patient. SAMe was discovered in 1952 as a chemical entity, but it was not until 1974 that it was first produced on a commercial scale for human therapeutic use. This represents the fact that initially, nobody saw its potential as a therapeutic agent. As its chemistry was better understood, it was appreciated that its function was central to many of the vital rate lim iting processes within the cell. The decision was taken to promote it as a therapeutic agent in several different therapeutic fields, and the hugely expensive mechanism of getting pharmacological approval was initiated. It is noted that it was originally investigated and approved in Italy, and this is the reason for the fact that the majority of the early work has Italian authorship. In 1974, initial approval was granted and large scale trials began. In this dissertation we have discussed the evidence that SAMe is effective in cases of depression. A considered overview of all of the available evidence would have to conclude that it does not appear to have any significant therapeutic advantage over any of the other currently available antidepressants in terms of efficacy. The majority of the studies that have compared SAMe with another agent have shown that both work better than a placebo with a few percentage points difference between them. Almost without exception, the studie s that have been reviewed are really quite small in terms of entry cohort and therefore are not suitable for major extrapolations in terms of efficacy comparisons. The two meta-analyses that we have presented are also flawed in this respect and although positive trends can be identified, the statistical validity is certainly not up to the standards that we would expect if they were published in a contemporary peer reviewed journal today. Where SAMe does appear to have a major clinical benefit over its competitors is in its side effect profile. It does appear to be extraordinarily safe and free from significant side effects. The only real contraindication that we have seen is when it is being considered in patients who have a history of mania or in the presence of bipolar disorder. Even then, it does appear to be a comparatively unusual event. Some studies have reported nausea. This is thought to be a centrally mediated effect as it has been shown to exert a protective effect on t he gut lining having been used, transiently, as an ulcer-healing agent. In terms of specific types of depression, we have presented evidence that SAMe appears to work in certain types of depressive states more predictably than in others. It seems to be at its most useful therapeutically, in states of primarily endogenous depression. To a lesser degree it has an effect in those depressive states which can be associated with the degenerative dementias. There seems to be little direct evidence that it has a significant effect in the reactive forms of depression. From what we know about the neuropharmcology of SAMe, this would appear to be both logical and, to an extent, predictable. As far as the endogenous depressions are concerned, it is thought that they are primarily caused by various metabolic disturbances within the neuronal pathways of the brain. We know that, on a simplistic level that this is where SAMe has its prime effects. We know that it has various trophic effects on the neuroexcitatory pathways and it does therefore not require a huge leap of faith to see that it could work in these situations. Reactive depression is not thought to be a straightforward chemical abnormality in the brain, but it a reaction to external events, and therefore is more likely to be mediated by inhibitory triggers coming from the higher intellectual centres in the brain possibly working through the hippocampus. Again, it does not require a huge insight to appreciate that SAMe might be less effective in those circumstances. Many of the degenerative dementias are thought to be due to (in part) a failure of the methylating processes in the neural tissues. These are generally associated with neuronal destruction, so significant improvement in cognitive function simply would not be expected. 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A., Du, F., et al (1999) Hippocampal mossy fiber sprouting induced by chronic electroconvulsive seizures. Neuroscience, 89, 157-166 Zuess J 2003 An Integrative Approach to Depression: Part 1Etiology Co mplementary Health Practice Review, January 1, 2003; 8(1): 9 24. DonÃ¢â¬â¢t waste time! Our writers will create an original "S-Adenosyl-Methionine (SAMe) And Improved Methylation Offer A Serious Alternative To Orthodox Medications Health Dissertations" essay for you Create order