Satisfying Customers Needs And Wants Marketing Essay

Satisfying Customers Needs And Wants merchandise EssayMarketing has often been defined in terms of red-blooded customers needs and wants. Critics however maintain that trade goes beyond that and creates needs and wants that did non exist before, According to these critics, marketers encourage consumers to spend more money than they should on goods and service they really do not need.Marketing process can be explained as creating value for customers and building customer relationship by doing this the plaque makes winningsThe various elements of merchandising process can be classified as followFig 1Understanding the market place and customers needs and wants is achieved through with(predicate) in-depth market research and thereby identifying a product gap or needs gap. This lead involve trends , how to make things easier , comfortable, better and user friendly. In the archeozoic 80s there were few or no fluid phones. A thorough market research has created the need for mobile phones, thusly came the massive first coevals mobile phones.This were later followed by smaller ones and these days we can see the smart phones with inbuilt cameras, time online movies and overbolds ability to actual work from your mobile Samsung note to the new tablets.Every day specialist market research companies, innovators, technicians and scientist all work hand on hand to create a new niche market or brand that makes our lives much more comfortable. Even the pay as you go concept became appargonnt as people could not continue to pay the incredible racy cost then been charged by manufacturers who were looking at ways to cover the cost of their research and development. So the critics may not be far from the truth but the standard is marketers coming with ways and products that makes our lives easy.Design a customer driven marketing strategy. Marketing strategy is a long term means of achieving a corporate objective. If we take the example of the mobile phone industry whe re the likes of Samsung, IPhone, Nokia argon in unspoiled competition each as to design a marketing strategy to capture a share of the market. Like a military personnel volition define the art of going to warfare.Marketing program that delivers superior value This refers to the marketing mix that is the 4ps Usually referring to E. Jerome McCarthys14 P classifications for developing an effective marketing strategy, which encompasses product, price, placement (distribution) and promotion. When its a consumer-centric marketing mix, ithas been extended to includethree more Ps people, process and physical evidence, andthree Cs cost, consumer and competitor. Depending on the industry and the manoeuvre of the marketing plan, marketing managers will take various approaches to each of the 4 Ps.The benefits and cost of marketing orientationMarket orientation is the understanding of customers requirement and humanity of marketing mix which will meet these needs. Market driven means the firms capability to understand, attract and keep valuable customersG. Armstrong and P. Kotler define marketing as tender and managing processby which the individuals and groups procure what they need by creating and exchanging values with others.2A market-oriented company is in a position to achieve competitive advantage give thanks to its unique innovative approach to customers. In addition to this,according to the opinion of P. R. Dickson, a competitive advantage should beunderstood in the sense of kinetics of competition. He expresses disagreementwith the standpoint of neoclassic theory of market equilibrium and claimsthat the main characteristic of the market is its disequilibrium. He sees marketingas a scientific discipline and skill of creating changes (disequilibrium) in the market inthe manner that would provide for the changes that are beneficial for the company.Various responses of salespersons and customers to changes in supply anddemand, thinks Dickson, create possib ilities that could be used by the companythat understands market. He underlines the importance of adjusting companyto the market occurrences.3Benefits and cost of market orientationFigure 2 Customer relationship groupsSource G. Armstrong, P. Kotler, Marketing An Introduction, 7. ed., Pearson/Prentice-Hall, speed Saddle River, NJ, 2005, p. 25.The above summaries the benefits and cost of market Orientation other advantages and disadvantages.Responding to DemandBuilding Customer ValueDisadvantagesExtensive and Expensive Research and Incr residuumd cost. small and Macro environmental factors that affect marketing DecisionThe micro environmental factors are factors that can be controlled by the organisation and relates directly with the business these are considered using the factors in fig 3Micro Environmental factorsFig 3Fig 4 shows how different public affects organisation. The public that affect the marketing decision of the yet they can be controlled and are regarded as micro are th e relation with the following members of this public e.g Financial public this is based on say for example the organisations annual returns.Fig 4Macro Environmental FactorsThe Target market for mobile phones companies and IT companies are more likely to be the high income earning spectrum of the society or the new graduates and the city bankers and young people in the top echelon of society who will be able to afford the integrated cases that are about(predicate) to be launched into the market very soon The package will include home entertainment, office package, security package, phone and video calls and financial/banking package all launched as one integrated hand held device.Market segmentation, and Target is followed by positioning, this should be developed and implemented by creating an image for the product, profiling the come in market,High Tech gadgets like this integrated hand held device will be bought based on the technical specification what comfort or ease of doing a task it provide.Buying Behaviourur is the way and act of people involved in buying and using products. To understand these we need to consider, why a emptor will make a purchase, what factors influence will influence a buyer to buy a certain product.Buying Behaviour refers to how people will be urinate when buying a certain product.A firm needs to consider and study buying behaviourur and peoples reactions to the organisation marketing strategy has this will have great impact on the firms success.The marketing concept show how a marketing mix (MM) that satisfies (gives utility to) customers, hence it important to understand the what, where, when and how consumers buy.Stages of the Consumer Buying playThere are Six Stages to the Consumer Buying Decision Process (For complex decisions).Problem RecognitionInformation searchThe evoked set.Evaluation of AlternativesPurchase decision- smirch Purchase decisionBuying behaviour is often goaded by the level of consumer involvement in the purchase decisions, the importance and level of interest the consumer decisions is determined by the motivation to seek information about the product or service. High involvement purchase such as buy a prodigality car or other expensive items. Also the element of risk involved in the use of the product that is the social risk and the economic risk.The four type of consumer buying behaviourRoutine Response/Programmed Behaviourr, Limited Decision Making, Extensive Decision Making/Complex, impulse buying, Routine Response/Programmed behaviour this are low involvement very little or no decision effort is required E.g. A can drink .Limited Decision Making- This are product bought occasionally example are like clothing but not brandsExtensive Decision Making/Complex This involves unfamiliar, expensive and infrequently bought goods. It involves a high degree of economic performance, and psychological risk. e.g. cars, homes, computers, it also involves a lot of time seeking information an d deciding. and consumers will go through all six-spot stages of the buying process.Impulse buying, this are purchase which are unplanned it like buying chewing gum in the Conner shop without actually thinking about it. Also prices at time lead to impulse buying. They are usually low valued items.Ethan Lyon said The goal of market positioning is to find the ideal opportunity in the market based on customer needs, market forces and financial and strategic considerations. Once the market opportunity is identified then the organisation can further develop its product and elevate its brand to deliver outstanding value. To clarify the market position, the firm will need to find an overarching theme, then define the details. (sparxoo.com)Brand Idea-The idea is an aspirational concept it defines the idea of what the company. For example the Samsung note goes with the concept of designed for humanValue Proposition- A customer or a consumer buyers the Samsung note they see high value and hi gh qualityDifferentiating Attributes-Samsung has distinguished itself from Apple by targeting the main stream yet providing quality and comparable or better phones than those provided by AppleWord count1450

Analysis of SAMe as an Antidepressant

Analysis of equivalent as an AntidepressantS-Adenosyl-Methionine ( corresponding) And Improved Methylation Offer A ripe Alternative To Orthodox MedicationsCan S-Adenosyl-Methionine ( equal) and improved methylation offer a serious alternative to orthodox medications in the discourse of slack?AbstractIn this language we grapple the takes surrounding the employ of equivalent as an antidepressant drug. There argon m whatsoever distinguishable aspects to this affection.We scratch line by a consideration of exactly what yield is on a clinical basis and get a bandagedary the psychological and physiological changes that characterise the condition. We consequently consider and examine the evolution of the current radiation patterns of antidepressant medication.We search the fields of neurochemistry and pathophysiology of depressive relegates with particular emphasis on the chemistry of the methylation response and its relevance to the comparable compound.Consideratio n is then given to SAMe specific all in ally as a medication and the evidence that at that place is to assist its app bent beneficial effect in feeling. This is then grow with a review of the chemistry of SAMe and its inter carry throughs with separate biologically active entities.We conclude the exploration with a critical review of the published literature that is germane(predicate) to the affair of SAMe as an antidepressant agent.presentationIn order to investigate the full extent of the question at the heart of this dissertation we must examine a take of background issues in nigh detail first. Depression is a complex clinical res publica. It has been said that there argon as m any(prenominal) theories nigh the aetiology and treatments for depression as there are clinicians view about the problem. (LeDoux, J. 1996). A brief examination of the literature on the airfield tells us that this comment, although clear intended to be flippant, whitethorn not truly 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 in any case a broad number of forms of treatment that are publicly employed. It has to be admitted that almost are rational and some reckon to be completely irrational. In this dissertation we shall examine some of the to a greater extent rational forms of psychopharmacology in order to understand the place of SAMe in the curative pharmacopoeia.Depression is a commonly occurring illness. It will signifi undersidetly affect between 10-25% of women and approximately half that number of men during their lifetimes. Approximately 5 million throng in the UK will experience signifi kindlet depression in any given year. (Breggin 1994)If you suffer from an acute or chronic illness you are redden much liable(predicate) to suffer from depressive states with frequencies ranging from 30-50% depending upon the nature and bitterness 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 serious to distinguish between clinical depression and simply crediting d rent or miserable. Depressive illness typically occurs in episodes although in some cases it lav actually last for many months or even years. (Skolnick, P. 1999). One heavy depressive episode is a study freelancer risk incidentor for getting further episodes. In an some other(prenominal)(a) words, having had depression once you are statistically considerably much belike to have some other attack. (Post RM. 1992).For our purposes we shall consider a practical overview of the nine guileless symptoms that characterise classical depression1. Depressed mood for more or less of the day2. Disturbed appetite or change in weight3. Disturbed pause4. Psychomotor retardation or agitation5. Loss of refer in previously pleasurable activities in en ergy to enjoy usual hobbies or activities6. Fatigue or loss of energy7. Feelings of ineffectualness excessive and/or inappropriate guilt8. Difficulty in concentrating or thinking understandably9. Morbid or suicidal thinkings or actions.(After Zuess 2003)The Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) states that in order to merit a diagnosing of clinical depression you lease 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 dispirited forbearing 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 install in bipolar states (manic depression). Subjective feelings of focus or irritability are often depict as closely as respectable sadness. (Duman et al 1997)In asset to mood c hanges, depression can also produce changes in the emotional state as well. Feelings of worthlessness and guilt are peradventure the comm whizzst emotions in the clinical spectrum. This is closely fol starting timeer-rankinged by twain ineptitude and lack of confidence in ones consume abilities or capabilities. It is common for depressed great deal to take action that avoids them having to take responsibility because of an raise tutelage of failure. (Altar CA 1999) bodied manifestations of depression are perhaps easier to quantify as they have a qualitative characteristic about them as opposed to the stringently subjective. Changes in appetite are commonly build. primarily it is an anorexic change with a decrease in appetite and a loss of interest in food generally. Less frequently, the converse is observe with a voracious increment in appetite (comfort eating) which is normally associated with weight gain. This weight gain can be quite substantial in extreme cases. cess ation painances are commonplace. Insomnia and early waking are perhaps the commonest of this casing of symptom. This can occur despite severe subjective symptoms of somatic tiredness and fatigue. few people will understand that fatigue is a prominent symptom and whitethorn find that this is translated into excessive quiescency and motor retardation generally.Fatigue is actually more difficult to quantify, and it is commonly experienced by the depressed patient. It can either be an overwhelming tiredness (lack of energy) or perhaps lack of staying power (tiring too easily). Associated with this is often a reduction in libido and, if severe, impotence can also occur. It is not eccentric 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 tightfistedness impairment. Thinking and reasoning processes slow down and the f ear span is often markedly reduced. Students find they can have an softness to ascertain and if severe, patients traverse an softness 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 demurral or minimisation where they will not accept that they are actually depressed. They can try to snub 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 other underlying pathology), then psychosis can be found. neurotic 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 wi th 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 sock that a number of different biological factors are applicable. environmental factors, together with both genetic 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 opinion 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 practicable actions of SAMe. (Gold et al 1988)Pharmacology of depressionThis is a vast subject and is generally considered to be a sub-speciality in its own right. It has tenacious been recognised that certain substances bulge to be able to assert a mood elevating effect. The advent of stylern psychopharmacology allowed us to develop an understanding into just how some of these substances puddle. 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 recorded bill and progressed to the chemically and biologically school 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 use antidepressants work by interfering in some way with the actions of the unlike neurotransmitters in the brain. some(prenominal) work by slow down the biological processes of degradation or destruction of these neurotransmitters. In purely simplistic terms, this results in a greater con centration of the neurotransmitter at the critical synaptic interfaces in spite of appearance the brain. (Levine et al 1998)The first real breakthrough with what could be considered to be a major healing(p) agent for depressive states came with the find of the MAOI (Monoamine Oxidse Inhibitors), chemical group of drugs. collar were commonly use 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 lethal side effect. (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 tall mallow 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, viz. amitriptyline, desipramine, imipramine and nortriptyline. These were generally speaking, marginally more effective than the MAOIs but they were without the worst of the side set up. Despite that, they were liquid 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 also had hypertension. The pharmaceutical exertion 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 turning point the biggest share of the clinical market with citalopram, escitalopram, fluoxetine, paroxeti ne and sertraline as examples of the group. Fluoxetine was probably the most widely used and its trade list, 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 overleap into disuse largely because of their reputation in elevator cholesterol levels and the NDRIs were found to cause unacceptable agitation in certain groups.There was then an increment of a group of drugs which not only obstruct the implements 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 depressionSo 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, dialect and antidepressants emerge to have reciprocal actions on neuronal growth and to some extent, on their activity (see on). This appears to be through the intermediation of various neurotrophins and the action of synaptic plasticity mainly in the division of the genus 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 swear outal groups, or networks of neurones whereas antidepressants appear to antagonise this dissolute 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 forge 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 probably 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 stallular 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 presenc e 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 hold that it does play an significant contributory subroutine. 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 takings 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 fin ding of increases in the levels of messenger RNA which codes for the cAMP response element screening protein (CREB). These levels slowly increase with chronicity of administration of antidepressants and this mechanism may well account thereof 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 Derived 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 instantaneously 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 entangle 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 explorative behaviour in rodents tends to diminish if a depressive state is induced. To some extent, explorative 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.Many of the neurotransmitters and for that matter some neuroactive internal secretions have been variously concerned 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 attached 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 high func tions 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 depression the hippocampus has fewer corticosteroid receptor sites than one index 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 medicationSAMe was discovered in Italy in 1952 during research into the chemistry of neurotransmitters. It was not, however, introduced in a useable form for patient proce eds 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, degenerative arthritis 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 troika 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 Vann a 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 manage 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 tribulation 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 appear s 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 have a bun in the oven other forms of antidepressants or, for that matter, have had minimal response to them.(Reynolds et al, 1984) recent (1993) produced a particularly provoke 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 combi nation 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 running game 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 cash advance in the SAMe group when co mpared 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, it 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 standby medication.The study by Berlanga (et al 1992) did exactly that. unluckily 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 depression) 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. some other 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 perplexity insofar as in the men in the trial group had their levels of TSH and Prolactin reduced which is consistent with the hypothesis that SAMe increases the dopamine levels in the brain. Much to everybodys surprise, this effect was not seen in the female person group. The authors do not offer any explanation of this fact.For the record, there is another trial (Thomas et al 1987), which simply considered the same phenomenon and their trial did not show any sex linked difference in the suppression of the Prolactin levelsWith 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 depress ion. 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 believe 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 B12, B6 and folic acid. It is known that SAMe is essential 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 obligatory for the intracellular conversion of methionine into SAMe by the proviso 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.ChemistrySAMe is a basic component of cellular biochemistry. It occurs in every living cel l and is second in importance only to adenosine triphosphate 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 reactionsIt 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. (Baldess arini 1987). importantly 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 role 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 trigger it, and thereby beginning a synthesis or degradation process elsewhere in the cell. equally removing the methyl group will render the enzyme unreactive 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 ef fectively modulate 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 MAT (methionine adenosylAnalysis of SAMe as an AntidepressantAnalysis of SAMe as an AntidepressantS-Adenosyl-Methionine (SAMe) And Improved Methylation Offer A Serious Alternative To Orthodox MedicationsCan S-Adenosyl-Methionine (SAMe) and improved methylation offer a serious alternative to orthodox medications in the treatment of depression?AbstractIn 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 character ise 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 interactions 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.IntroductionIn 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 aetiolog y 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 f rom 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 although 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 depression1. Depressed mood for most of the day2. Disturbed appetit e or change in weight3. Disturbed sleep4. Psychomotor retardation or agitation5. Loss of interest in previously pleasurable activities inability to enjoy usual hobbies or activities6. Fatigue or loss of energy7. Feelings of worthlessness excessive and/or inappropriate guilt8. Difficulty in concentrating or thinking clearly9. Morbid or suicidal thoughts or actions.(After Zuess 2003)The Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) 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 wei ght 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 difficult 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 s low 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 t his 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 genetic 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 depressionThis is a vast subject and is generally considered to be a sub-speciality in its o wn 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 recorded 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 concentra tion 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 co mmon 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 also 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. Fluox etine 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 levels 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 o f a therapeutic dose of this medication. (Harmer et al 2003)Neurochemistry and pathophysiology of depressionSo 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 develop ment 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 el ement 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 Derived 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 s ignificant 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.Many 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 th at 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 depression 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 medicationSAMe 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 earl y 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 wh ich 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 th at 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 benefic ial 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, it 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 resolv ed 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 depression) 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 level s 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 hypothesis 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 levelsWith 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 biochemica l 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 B12, 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.ChemistrySAMe 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 reactionsIt 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 a nd 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 th e 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 activating 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. B y 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 MAT (methionine adenosyl

Cavemen :: History

In early times, cavemen lacked useful tools to communicate and survive. Their early weapons were brittle and make it difficult to successfully hunt. They were always on the move, traveling to find food and shelter. Because of these things, groups of cavemen remained small. The caveman eventually overcame these problems and grew to be civilized. The caveman made many great advances throughout history.Some entire things that cavemen discovered were fire, hunting weapons, tools, and a verbal language that was much more complex than their animal ancestors. The first discovery, fire, provided them with warmth and protection, light, and heat to cook things. The second, hunting weapons, were made mostly of flint and dulled easily. The third advance was tools. They had tools that helped them in hunting and farming. Because they now had tools for farming, they could remain more stationary than their ancestors. Their language, consisting of only syllables, allowed them to communicate with le ss chip than their predecessors.The reason these advances were so great was that they provided them the stepping stone for becoming civilized. They could now remain in one location instead of being nomadic. The tools they had for farming allowed them to make factory farm worth the effort. It also gave them much free time to work on other things such as inventing the wheel. They also developed art, which shows us their higher take of thought.The cavemans discoveries changed peoples way of life for years to come.

Capital Punishment Essay -- essays research papers fc

corking penalty is a method of retributive punishment as old as civilization itself. Anti-death penalisation supporters turn everyplace the death penalty is unconstitutional. Capital punishment is a barbaric remnant of an uncivilized society. It is immoral in principle, and unfair, and discriminatory in practice. It assures the execution of nearly inculpable plenty. As a remedy for law-breaking, it has no purpose and no effect. The arguments against capital punishment are many and cogent.Capital punishment is irrevocable, and the errors of justice can non be rectified. solely(a) possibility of reconsideration is taken away. Innocent persons look at been hanged, and judge, jury, and the legal machinery involved have thereby been made a privy to the very crime they seek to punish. The only way to repeal a criminal is by reforming the man who is a criminal. To destroy a criminal is by reforming the man who is a criminal. To destroy his bodily life is nothing but a stupid b lunder.The strongest argument against using capital punishment for retributive purposes, is the argument that capital punishment is uncivilized and unusual punishment. The Eighth Amendment of the United States Constitution, condemning criminal and unusual punishment, is used to protest capital punishment. Officials often defend this punishment as not world cruel and unusual, but how can they defend this opinion in the case of John Evans, who was executed by electrocution in 1983? According to witnesses at the scene, Mr. Evans was attached three charges of electrocution over a period of fourteen minutes. After the first and second charges, Mr. Evans was still conscious and smoke was coming from all over his body as a result of flesh burning. An official there even tried to stop the execution on account of it universe cruel and unusual punishment, but was unsuccessful. Witnesses later called the whole incident a barbaric ritual. Studies show that in this century at least four-hun dred innocent people have been convicted of capital crimes that they did not commit, and of those four-hundred, twenty-three were executed. The wrongful execution of an innocent person is an injustice that can never be rectified. Maybe the punishment would not be as bad if there was absolute surety that the person the jury was putting on death row was guilty, but as most... ...nbsp decennium Commandments tuner program delivered in the early 90s.Gross, R. and Robert Mauro. Death and Discrimination. Northeastern University Press, 1989Bohm, Robert M.. ed. The Death Penalty in America Current Research. Anderson Publishing Co., 1991Radelet, Michael L. ed. Facing the Death Penalty. synagogue University Press, 1989 Capital Punishment Essay -- essays research papers fc Capital punishment is a method of retributive punishment as old as civilization itself. Anti-death penalty supporters argue the death penalty is unconstitutional. Capital punishment is a barbaric remnant of an uncivilized society. It is immoral in principle, and unfair, and discriminatory in practice. It assures the execution of some innocent people. As a remedy for crime, it has no purpose and no effect. The arguments against capital punishment are many and cogent.Capital punishment is irrevocable, and the errors of justice cannot be rectified. All possibility of reconsideration is taken away. Innocent persons have been hanged, and judge, jury, and the legal machinery involved have thereby been made a privy to the very crime they sought to punish. The only way to destroy a criminal is by reforming the man who is a criminal. To destroy a criminal is by reforming the man who is a criminal. To destroy his bodily life is nothing but a stupid blunder.The strongest argument against using capital punishment for retributive purposes, is the argument that capital punishment is cruel and unusual punishment. The Eighth Amendment of the United States Constitution, condemning cruel and unusual punishment, is used to protest capital punishment. Officials often defend this punishment as not being cruel and unusual, but how can they defend this opinion in the case of John Evans, who was executed by electrocution in 1983? According to witnesses at the scene, Mr. Evans was given three charges of electrocution over a period of fourteen minutes. After the first and second charges, Mr. Evans was still conscious and smoke was coming from all over his body as a result of flesh burning. An official there even tried to stop the execution on account of it being cruel and unusual punishment, but was unsuccessful. Witnesses later called the whole incident a barbaric ritual. Studies show that in this century at least four-hundred innocent people have been convicted of capital crimes that they did not commit, and of those four-hundred, twenty-three were executed. The wrongful execution of an innocent person is an injustice that can never be rectified. Maybe the punishment would not be as bad if there was absolute surety that the person the jury was putting on death row was guilty, but as most... ...nbspTen Commandments radio program delivered in the early 90s.Gross, R. and Robert Mauro. Death and Discrimination. Northeastern University Press, 1989Bohm, Robert M.. ed. The Death Penalty in America Current Research. Anderson Publishing Co., 1991Radelet, Michael L. ed. Facing the Death Penalty. Temple University Press, 1989

The V-chip :: essays research papers

The V-ChipWhat is a V-chip? This term has become a buzz word for whatsoever discussion evolvingtelecommunications regulation and telly ratings, but not too m whatsoever reportsdefine the refreshing technology in its fullest form. A basic definition of the V-chipis a microprocessor that can decipher knowledge sent in the vertical blankingof the NTSC signal, purposefully for the control of violent or controversialsubject matter. Yet, the span of the new chip is much greater than any workingdefinition can encompass. A discussion of the V-chip must include aconsideration of the technical and ethical issues, in addition to examining theconstitutionally of any law that might concern standards set by the USgovernment. Yet in the space provided for this essay, the focus go forth be thetechnical aspects and costs of the new chip. It is impossible to generallyassume that the V-chip will solve the violence problem of broadcast televisionor that adding this little device to every set will be a first amendmentinfringement. We can, however, find clues through examining the cold facts ofbroadcast television and the impact of a mandatory regulation on that freebroadcast. "Utilizing the EIAs Recommended devote for Line 21 DataService(EIA-608) specification, these chips decode EDS (Extended DataServices)program ratings, compare these ratings to viewer standards, and can beprogrammed to take a variety of actions, including complete blanking ofprograms." Is single definition of the V-chip from Al Marquis of Zilog Technology.The FCC or Capitol Hill has not set any standards for V-chip technology thishas allowed many different companies to construct chips that are similar in so far notexact or possibly not compatible. Each chip has advantages and disadvantages forthe ratings system, soon to be developed. For example, some units use onscreenprogramming such as VCRs and the Zilog ingathering do, while others are consideringset top options. Also, different companies a re using different methods ofparental control over the chip.Another problem that these new devices may incur when included in everytelevision is a space. The NTSC signal includes extra information space known asthe subcarrier and Vertical blanking interval. As explained in the quotationfrom Mr. Marquis, the V-chips will use a certain section of this space to sendsimple rating numbers and points that will be compared to the personalitysettings in the chip. Many new technologies are being developed for smart-TV ordata broadcast on this part of the NTSC signal. Basically the V-chip willseverely limit the bandwidth for soaring performance transmission of data on theNTSC signal. There is also to be cost to this new technology, which will be

PESTEL Analysis :: Business, External Environment

PESTEL AnalysisThe PESTEL analysis is an important and widely-used tool for understanding the heroic picture of a firms external environment. PESTEL is an acronym for the political, economic, socio-cultural, environmental, and legal environment in which a firm operates. The benefits of the PESTEL analysis are that it helps identify potential environmental influence, helps better understand existing opportunities and threats, and helps understand market growth and decline. PoliticalThe political environment has an influence on business. Political factors need to be considered when consider the external environment. According to Binstock, Clorox is voluntarily converting its plants in the United States to safer chemical process in order to protect against disasters and terrorism ( 2010). More than 200 chemical facilities crosswise the U.S. have converted to safer chemical processes. In the same article, it said that in 2006 congress passed a temporary law that bars the government fro m requiring disaster prevention. This is substantially publicity for the alliance and puts it ahead of its competitors if the government ever puts disaster prevention laws in to place.EconomicEconomic factors are important to Clorox because these factors affect the companys profits. Cloroxs main economic concern appears to be increasing raw material cost. Significant increases in the costs of energy and transportation, including the cost of diesel, or of get a line raw materials, including, but not limited to, resin, chlor-alkali, sodium hypochlorite, corrugate, agricultural commodities and other raw materials (Clorox, 2010). A rise in the price of raw materials could force the company to raise prices to keep making a profit. A struggling economy could reduce consumer spending. Sales totaled $1.27 billion, down 2.8 percent from the same quarter a year ago (Avalos, 2010).Socio-culturalTodays consumers are very environmentally conscious. The company is taking advantage of this by p roducing environmentally friendly products. The company has change magnitude its profits through the sales of its Green Works product line. According to an article from the San Francisco Chronicle research says that Green Works accounts for about half that $ coke million annual market for eco-cleaners (Said, 2010). Customers like company that give back to the community. Clorox does this through the Clorox Foundation. The mission of The Clorox Company Foundation is to improve the quality of life in communities where Clorox employees live and work (Clorox, 2011). TechnologicalTechnology factors play a major role in what opportunities a company faces. The Company has outsourced a significant percent of its information technology activities to Hewlett-Packard, including its data centers, which are primarily located in Alpharetta, Ga.

Bontsha And Gimpel :: essays research papers

Faith is believed to be one of the most important elements attached to the life of a compassionate being. Faith brings meaning to life. It is the essence that ties a person to life no matter the struggle encountered. Whenever some one looses faith in the people of their society, all he has felt is a sacred believe which can be translated into &8220faith in God(s). In the stories &8220Bontsha the Silent and &8220Gimpel the Fool by Isaac Loeb Peretz and Isaac Bashevis Singer respectively, the protagonists are victims of tremendous sufferings, where faith is the only way out. However, the faith centre by both authors differ somewhat. Peretz prioritizes faith in the divine, while Singer elaborates faith in man around their protagonists.First, in his tale &8220Bontsha the Silent, Peretz seems to suggest that a person who has unconnected faith in man ought to have, at least, faith God. One must not go without faith just because he had black market into some sort of difficulty or been victim of injustice during his life. Peretz expresses his believe through the main theatrical role, Bontsha. He describes Bontsha as the most unfortunate imaginable human being on earth and yet never complaining about his adversity. Ever since the first day Bontsha was born, no one has cared of him. He was born with still and passed away with silence. During his lifetime, he had to haul heavy loads stumbling at each step and begged for the pennies that were rightfully his, and even so, sometimes he did not get paid. Further, he knew he had been taken advantage of, and still, he remained silent. Once he had run into luck by saving a man&8217s life who then made him a coachman and married him off. But his luck did not last for long, as his great benefactor and philanthropist went into bankruptcy and never got what he had earned. Peretz develops his character in such way implying that perhaps Bontsha had so much faith in God that he did not care any of his sufferings he lost hope w ith mankind. When all faith for man is lost, one should at least believe in God for he might be rewarded in &8220the otherwise world. Indeed, when Bontsha dies, he rewarded for having maintained his faith in God and never complained to him.Second, in &8220Gimpel the Fool, Singer demonstrates the importance of faith in man one must have.