donepezil hydrochloride

donepezil hydrochloride Abstract- This article describes the discovery processes of donepezil hydrochloride which is inhibitor of acetylcholinesterase enzyme. Cholinergic hypothesis and other studies proved that deterioration in cognitive functions in Alzheimer disease is due to deficit in cholinergic neurotransmission and target to treat Alzheimer disease is to inhibit acetylcholinesterase enzyme. Position emission tomography (PET) study has shown that donepezil distributes in all acetylcholineterase rich brain regions and binds to it. Structure activity relationship (SAR) and quantitative structure activity relationship (QSAR) has also revealed that donepezil hydrochloride is gives optimum actylcholinesterase inhibition activity than its other analogues. Many methods are available for synthesis of donepezil hydrochloride with their merits and demerits. Keywords- Donepezil hydrochloride, Aricept, acetylcholinesterase inhibitors, PET study, indanone derivatives. Abbrevations AD(Alzheimer disease), PET(position emission tomography), QSAR(quantitative structure activity relationship), Acetylcholinesterase inhibitor(AchEI), Aim To study different processes involved in drug discovery of Donepezil hydrochloride. Objectives- The main Objectives of this project are given below To study overall literature review of donepezil hydrochloride . To discuss discovery process involved in discovery of donepezil hydrochloride such as target identification, target validation and lead optimization Introduction- Donepezil hydrochloride is the reversible acetylcholinesterase enzyme inhibitor having N-benzylpiperidine and indanone moiety in it (Sugimoto Hachiro et al, 2008). It is referred as E2020 in most of the pharmaceutical literatures. This is the second drug approved by U.S FDA for treatement mild and moderate Alzheimer disease (Stahl Stephen M et al, 2006). It is Patented and marketed in United states of America, some European and Asian countries under the trade name Aricept by Eisai.co.,Ltd (Stahl Stephen M et al, 2006) (Tripathi KD , 2006) (Dale Rang H et al, 2006). Drug Discovery of donepezil- The drug discovery process of donepezil involves various phases as follows Target identification Target validation Lead recognition Lead optimization Target identification Target identification of drug means molecular recognition of site to which it will bind. For many drugs target is protein molecules. Target identification needs information about pathophysiology of disease and identification of particular biochemical steps that leads to therapeutic intervention. Conventional stratergies of target identification are mainly based on pathphysiology of disease. But newer stratergies of target of identification are based on proteonomics and genomics (Rang H PB et al, 2006). About 50-60% of Alzheimer disease patient are of over 65 year age (Sugimoto Hachiro et al, 2006). It is the neurodegenerative disorder with mean duration of 8.5 years between onset of action and death of patient (Sugimoto Hachiro et al, 2006). Symtoms of this disease includes gross and progressive impairement of cognitive functions. The most affected areas in the alzheimers disease are hippocampus and neocortex which are important for mental functions. Pathophysiology of disease consis ts of external deposits of amyloid precursors and intracellular formation of neurofibrillary tangles leads to neuronal synapses loss (Francis Paul T et al, 1999) Beta amyloid is the main component of sensile plaque formed by proteolysis of amyloid precursor proteins. Tangles are abnormally hyperphosphorylated tau proteins and regulated by balance between multiple kinases and phosphates. Hyperphosphorylation of tau proteins carry out sequestration of normal tau and other microtubule associated protein leads to impairment of axonal transport. This tau becomes prone to aggregation into insoluble fibril in tangles (Bartonili Manuala et al, 2003) (Andrisano Vincenza et al, 2003) According to cholinergic hypothesis, deterioration in cognitive functions in Alzheimer disease is due to degeneration of cholinergic neuron into forebrain and consequently decreased cholinergic neurotransmission in cerebral cortex and hippocampus (Francis Paul T et al 1999). Cholinergic neuron synthesizes acetylcholine, which is the acetic acid ester of choline. Acetylcholine is synthesized from the acetic acid and choline with the help of cholineacetylase. After stimuli vesicles discharge acetylcholine at the nerve ending and binds to postsynaptic receptors. Acetylcholine is stored into the synaptic vesicles which are accumulated at the nerve endings, also prevents its hydrolysis. Acetylcholine is hydrolises by acetylcholinesterase into acetic acid and choline(Tripathi KD 2006). Thus in Alzheimer disease cholinergic neurotransmission can be enhanced by inhibiting preventing the hydrolysis of acetylcholine, choline precursor,acetylcholine release facilitators ,M1 and M3 agonists ,Nicotinic agonistics but all these drugs were not effective to improve cognitive function in Alzheimer disease except cholinesterase inhibitors. Cholinesterase drugs have shown significant improvement in cognitive functions of Alzheimer disease. This has proved that cholinestera se inhibition is the main target to improve cognitive functions in Alzheimer disease (Sabbagha Marwan N et al, 2008) (Fisher Abraham et al, 2008). Target validation of donepezil- Target validation is the investigational approach by which potential drug target can be tested and given further reliability. Target validation is pharmaceutical approach in which influence of drug is observed. (Rang H PB et al, 2006). According to cholinergic and other studies acetylcholinesterase inhibition is the main target to improve imrove cogntitive functions in alzheimer disease patient. Okamaru Nobuyuki et al studied invivo binding of donepezil in the brain of alzheimer disease patient. They radiolabled donepezil as [11c-methoxy]-donepezil for position emission tomography imaging. Evaluation of binding and distribution of donepezil performed on mild and moderate Alzheimer disease patients. Normal control group volunteers had neither cognitive function impairements nor cerebrovascular lesions on magnetic resonance. PET study carried out after three months of neuropsychological medical examination. Region of interest analysis was carried for validation of regional distrubution of donepezil. PET images demonstrated that high volume of [11C]-donepezil distributed in all regions of brain like striatum, thalamus, striatum, and neocortex which are rich in acetylcholinesterase. Tissue time curves of [c11] -donipezil shown initial rapid uptake of donepezil in brain followed by gradual clearance in both elderly normal and alzheimer disease patients. Specific distribution volume was calculated from region of interest by metabolite corrected plasma time activity curve. Donezpezil shown linear regression on logan plot analysis in all brain region as shown in figure -1. (Okamura Nobuyuki et al, 2008) (Yanai Kazuhiko et al, 2003) Lead generation A lead compound is a new chemical entity that could potentialy developed into new drug by optimizing its valuable and minimizing side effect. High throught screening is mainly used for lead generation(Rang H P et al, 2006). Many drugs were trialed to improve the cognitive functions in Alzheimer disease like cholinergic agonist such as oxetremorine, choline precursor phosphatidylcholine but that were inffective. Numerous clinical trials carried out on acetylcholinesterase inhibitors such as physostigmine, this trial shown that this class of drug resulted in improvement of cognitive functions in Alzheimer disease patients. However these clinical trials also proved that physostigmine has poor brain Penetration and thus less active (Muramoto,M et al, 1979). In 1981 summers et.al gave intravenous injection of tacrine to Alzheimer disease patients which were until that time used as antiseptic. These doses of tacrine shown measurable improvement in alzheimer symtoms but tacrine had shown ma ny side effects such as hepatotoxicity( Farlow SI et al, 1992). Later then scientist focused on development of new acetylcholinesterase inhibitors. Research and development of donepezil started in 1983 in Eisai .co .Ltd. Kawakami et al started to develop nontoxic tacrine derivatives but they failed to develop such tacrine derivative. While random screening scientists observed that N-benzylpiperazine (compound-A) has moderate anticholinesterase activity which was previously being synthesized for antiarterial sclerosis(Kawakami Yoshiyuki et al 2000)). During subsequent screening Kawakami et al used benzylpiperazine as seed compound and synthesized around 700 derivatives. Succeeding this experiment, it was observed that increase in acetylcholinesterase activity by replacing n-benzylpiperazine with N-benzylpiperidine moiety(compound-B). It was also found that slightly increase in activity by replacing ether group with amide group(compound-C) and removal of nitro group from benzamide moeity (compound-D) decreases activity. ((Kawakami Yoshiyuki et al 2 000). From these results Kawakami et al synthesized benzsulfonyl derivative and found that it is a most potent acetylcholinesterase inhibitor than benzpiperazine derivative. Benzsulfonyl derivarive showed very selective activity towards acetylcholinesterase but very poor bioavaibility. On the basis of this result they used benzoylsulfonyl derivative as lead compound. In next screening they replaced amide moiety with ketone moiety and maintained activity. Then Kawakami et al synthesized various indanone derivatives among them he found that donepezil has good acetylcholinesterase activity and bioavaibility(Sugimoto Hachiro et al, 1992). STRUCTURE ACTIVITY RELATIONSHIP OF DONEPEZIL Indananone derivatives were tested on rat for acetylcholinesterase inhibition activity according to method of Ellman et al. donepezil structure is divided into four rings as follows. Part 1- Indanone ring Part 2 -linkage moeity Part 3- piperidine moeity Part4 -benzyl moiety Modification at Indanone moeity If indanone moeity is replaced with ÃŽ ±-tetralone ,1-benzene suberone , 5,6 dimethoxy indene greately decreased activity ,while 25 fold increased activity by introducing methxy group at 5,6 position of indanone moeity .Carbonyl group is important for activity.Introduction of methoxy group at R3 position increase in activity by 20 fold .A methoxy group at R4 position increases activityby 10 fold . also slightly increase in activity on substitution to of methoxy group at para position in the benzoyl group moeity enhanced binding to the active site of acetylcholinesterase enzyme(Camps Pelayo et al, 2008). 2) Modification at linkage moiety- Various bridging group between indanone and piperidine moeity were tested for cholinesterase activity. If both indanone and piperidine rings joined directly then it dicreases activity .Increase in acivity with different bridging group in the following order prophylene >methylene>penthylene> ethylene >butylenes. (Sugimoto Hachiro et al , 1990). (3)Modification at piperidine moeity- Activity is depend on location and no of nitrogen atom .Nitrogen atom at 1-position of benzpiperidine is important for activity since N atom at 4-position of benzpiperidine decreases activity .If piperidine ring is replaced with piperazine moeity .then it dicreases activity(Sugimoto Hachiro et al, 2008). 4)Modification at benzyl moeity- 3-position substituted benzyl derivative showed greater activity among -2,-3,-4, substituted reioisomers .If benzene ring is substituted with electron withdrawing nitrogen group and electron donating methyl group shows similar activity .Replacement of benzyl group with phenylethyl group and 2-napthyl group decreased activity(.Kawakami Yoshiyuki et al, 2000)( Sugimoto Hachiro et al, 1990). Lead development of donepezil Once lead compound is identified then it is optimized and characterized for different aspects such as QSAR (quantitative structure activity relationship), SAR(structure activity relationship),synthesis method . Synthesis of donepezil If any compound shows optimum activity in above lead optimization processes then that compounds enter in further stage of lead optimization process. For physicochemical properties, pharmacokinetic, pharmacokidynamic study of lead compound highly purified and large amount of drug is required. Therefore synthesis method for lead compound is important. Sugimoto and co-workers discovered method for synthesis of donezepil with an overall yield of 27.4%. This process involves synthesis of ÃŽ ±, ÃŽ ² substituted ketones(compound 11) from 1-indanone by aldol condensation. This unsaturation product is catalytically reduced by Palladium to compound (13) but this method needs subzero temperature (-78%) and very toxic chemicals, such as n- butyl litium.( Tsuchiya Yutaka, 1992). Also many other method have been reported, which are too time consuming or not suitable for large scale production. Stephen discovered efficient synthesis method for donepezil and its analogue. This method involves hydrogenation of pyridine analogues ( compound 7) by using platinum oxide [scheme 2, path A] which is very expensive .If platinum oxide replace with less expensive 5% palladium carbon then it synthesizes compound (8) and compound (11).(US patent 6252081). Chandrashekhar R et al developed economical and efficient method for donepezil synthesis (scheme 2, path ÃŽ ²). In first step they condensed 5,6 dimethoxy -1-indan 1-one [ compound 2] with isonicotinaldehyde compound(3) by modification in standard procedure .By this condensation they formed intermediate compound (6) with 95.8% yield. Afterward he carried out hydrogenation of pyridine ring by using palladium carbon then he observed two main impurities compound (9) and compound (10) due to competitive side reaction of carb onyl ring. In this method they not only maintained different reaction conditions like reaction time, hydrogen pressure, and different solvent but also hydrogenated compound (6) in methanol under hydrogen pressure with 90% yield and 98.5% purity. Final step of donepezil involves benzylation of compound (8). In benzylation nature of solvent and quality benzylbromide plays important role in controlling dibenzyl product ( Elati Chandrashekar R et al, 2006). If acetone, dichloromethane, acetonitril, isopropylether and dichloromethane gives very poor yield. Conclusion- In conclusion donepezil hydrochloride is the novel and efficacious cholinesterase inhibitor than other acetylchlinesterase inhibitors. Cholinergic hypothesis shown that cholinergic degradation is the main reason for Alzheimer isease. By target validation it is also proved that donepezil bind to the acetyl cholinesterase and inhibits it. By the target validation it is also proved that donepezil inhibits cholinesterase mainly into the cortical and other areas where high concentration of cholinesterase is situated Is Donepezil has strongly proved cholinergic hypothesis and Also shown that cholineterse inhibition is the main target for treatement of alzimer disease than acetylcholine agonists and acetylcholine precursor. After different structure replacement and attachment to the lead compound of donepezil it is also proved that donepezil has good specificity and activity than other analogues .QSAR study of donepezil and its analogues also shown that donepezil is strongly binds to cholin esterase than other indanone derivatives. Sugimoto and their co workers also synthesized different pyridine and indanone derivatives they also got good efficacy of the results . For donepezil synthesis different methods have been developed all have some disadvantages and problems regarding hydrogenation step. But chandrashekhar elati et al method has overcome this problems by modifying synthesis methods. Acknowledgement- I thanks to Dr Kevine Devine, Dr Annie Bligh, Dr Dhaya Perumal for their guidance to study drug discovery technology module and prepare project(Dissitation) on donepezil discovery processes.

Berkshire Hathaway Essay

ISSUES Warren Buffet invoked the substance-over-form concept to justify accounting for the GEICO and General Foods transactions as dividends distributions rather than sales of stock. Do you agree with Buffet that the substance of each of the proportionate redemptions was a dividend and not a sale of stock? In deciding how to account for an unusual or unique transaction for financial reporting purposes, should one consider the tax treatment applied to the transaction? Did Peat Marwick have a right to change its position on the proper accounting treatment for the stock redemptions? What factor or factors may have been responsible for Peat Marwick’s decision to change its position regarding these transactions? FACTS In 1983, GEICO announced plans to purchase several million shares of its outstanding common stock for $60 per share. Among GEICO’s largest stockholders was Berkshire Hathaway, Inc., an investment company. Executives of the two companies decided that Berkshire would tender approximately 350,000 if its GEICO shares in the stock buyback plan, which would allow Berkshire to treat the transaction as a proportionate redemption. In a proportionate redemption, the percentage equity interest of on company in a second company is maintained at the level that existed immediately before the transaction. For federal taxation purposes, the proceeds received by the investor company in a proportionate redemption are taxed as dividends by applying the effective intercorporate dividend tax rate. In 1983, that tax rate was approximately 6.9 percent. Berkshire also chose to treat the proceeds from the redemption of the GEICO stock as dividend income in its 1983 financial statements. Berkshire’s audit firm, Marwick, Mitchell & Company, approved that accounting treatment. In 1984, another company in which Berkshire had a significant equity interest,  General Foods, announced a stock buyback plan. Again, Berkshire structured the sale of stock to General Foods so that the transaction qualified as a proportionate redemption. Berkshire also opted to report the proceeds received from General Foods as dividend income in its 1984 financial statements. In late 1984, representatives of Peat Marwick told Berkshire executives that the proceeds of the General Foods stock redemption should not be considered dividend income for financial reporting purposes. Instead, Peat Marwick maintained that the transaction should be recorded as a sale of stock with the difference between the selling price and cost reported as a capital gain on Berkshire’s income statement. This treatment of the transaction was less favorable for financial reporting purposes that the option preferred by Berkshire since it did not allow the total proceeds received from General Foods to be reported as revenue. Peat Marwick’s recommendation annoyed Berkshire’s executives. The accounting firm’s next decision irritated those executives even more. Marwick insisted that Berkshire restate its 1983 financial statements to reflect the GECICO stock redemption as a sale of stock rather than as a dividend distribution. Warren Buffet, Berkshire’s CEO, discussed the GEICO and General Foods stock redemption at length in his company’s 1984 annual report. Buffet disputed Peat Marwick’s contention that the transactions should be treated as sales of stock and not as dividend distributions. He then explained why he eventually agreed to accept the audit firm’s position by saying â€Å"†¦to avoid a qualified auditor’s opinion, we have adopted Peat Marwick’s 1984 view and restated 1983 accordingly.† Buffet as confirmed that Marwick’s decision had no effect on Berkshire’s business with GEICO or General Foods, their cash, taxes, and market value and tax basis of our holdings all remain the same. However, treating the General Foods transaction as a sale of stock reduced Berkshire’s 1984 net income by 8 percent. Applying that accounting treatment to the 1983 GEICO transaction reduced Berkshire’s previously reported net income for 19 83 by 1 percent. The Wall Street Journal reported the disagreement between Berkshire  executives and Peat Marwick that evolved from the proportionate redemption transactions. When asked to comment on Buffet’s criticism of Peat Marwick in his company’s 1984 annual report, a Peat Marwick partner simply noted, â€Å"It’s the client’s prerogative to disagree. Our report speaks for itself.† Another prerogative of an audit client is to change auditors. In 1985, Berkshire retained Touche Ross & Company to audit its financial statements. As required by the Securities and Exchange Commission, Berkshire filed an 8-K statement with that federal agency to disclose the change in auditors. In that statement, Berkshire reported it was â€Å"dissatisfied† with Peat Marwick’s inconsistency regarding the proper accounting treatment for stock redemptions. AUTHORITY/ANALYSIS The substance over form accounting concept means that the economic substance of transactions and events must be recorded in the financial statements rather than just their legal form in order to present a true and fair view of the affairs of the entity. Preparers of the financial statements should use their judgment when employing the substance over form concept, which helps to derive the business sense from the transactions and events and to present them in a manner that best reflects their true essence. In some instances the legal aspects of transactions and events may have to be disregarded in order to provide more useful and relevant information to the users of financial statements. The concept of substance over form is imperative to the representation and reliability of information contained in the financial statements. A proportionate stock redemption is a transaction in which ownership interests are redeemed proportionate to the total shares outstanding. As a result, each shareholder owns the same percentage of the company after the redemption as before. Buffet was justified in recording each of the proportionate redemptions as a dividend and not as a sale of stock, because although GEICO and General Foods repurchased their stocks, Berkshire still maintained the same percentage of equity interest as it did before the transaction. Also, Buffet followed federal taxation purposes, which stated  that the proceeds received by the investor company in a proportionate redemption are taxed as dividends; therefore the transaction was recorded as dividends not sale of stock. By placing the responsibility on the preparers of the financial statements to actively consider the economic reality of transactions and events to be reflected in the financial statements, it will be more difficult for the preparers to justify the accounting of transactions in a manner that does fairly reflect the substance of the situation. According to the PCAOB’s AU Section 316.66, â€Å"†¦the auditor may become aware of significant transactions that are outside the normal course of business for the entity, or that otherwise appear to be unusual given the auditor’s understanding of the entity and its environment. The auditor should gain an understanding of the business rationale for such transactions and whether that rational (or the lack thereof) suggests that the transactions may have been entered into to engage in fraudulent financial reporting or conceal misappropriation of assets.† (PCAOB, 2002) AU Section 314.21 states that the auditors’ understanding of the entity and its environment consists of an understanding of several aspects, including industry, regulatory, and other external factors (PCAOB, 2002). Taxation would be an example of the regulatory aspect; therefore, one should consider the tax treatment when deciding how to account for unusual transactions. In the case of Berkshire Hathaway, Inc., since the IRS considers proportionate redemptions to be equivalent to dividend distributions, and the proceeds from the repurchasing of stock are taxed as dividends; to ensure consistency, the transaction should have been recorded as dividends. The PCAOB states that the auditor should recognize an adjustment to correct a misstatement in previously issued financial statements to ensure the company’s financial statements remain consistent in the auditor’s report, especially if the matter has a material effect on the financial statements (PCAOB, AU 508.16, 2004). Since Peat Marwick was the auditing firm, it had the right to change its position on the proper accounting treatment for the stock redemptions, and since Berkshire wanted to preserve the unqualified  opinion, the company complied with the auditors. In order for Peat Marwick to maintain its reputation as professional auditors and providing quality audits, the firm decided it was in their best interest to record the GEICO and General Foods transactions as sales of stock by Berkshire, rather than as the receipt of dividends. Under this accounting approach, a portion of the cost of the Berkshire’s investment in the stock of each company would be charged against the redemption payment and any gain would be reported as a capital gain, not as dividend income. This is an accounting approach only, having no bearing on taxes; although, Peat Marwick agreed that the transactions were dividends for IRS purposes. Since the change in accounting treatment reduced Berkshire’s net income by 1% and 8% in 1983 and 1984, respectively, Peat Marwick might have deemed this as material and thought it was necessary to correct the way the transactions were recorded. According to the PCAOB, in evaluating consistency of financial statements, the auditor should evaluate a change in accounting principle to determine whether: the newly adopted accounting principle under GAAP, the method of accounting for the effect of the change is in conformity with GAAP, the disclosures related to the accounting change are adequate, and the company has justified that the alternative accounting principle is preferable (PCAOB, AU 508.17A, 2004). Any of these factors may have been responsible for Peat Marwick’s decision to change its position regarding these transactions. Although recording the stock redemption as a dividend complied with taxation rules under the IRS, it may not have been in accordance with GAAP. Berkshire may not have justified that recording the stock redemption as a dividend was preferable. Although it was preferable to Berkshire, because total proceeds from General Foods would have been reported as revenue, increasing Berkshire’s net income; it may not have been preferable to all the users of Berkshire’s financial statements, because net income would have been over stated. Lastly, in Berkshire’s letter to its shareholders, it stated that the GEICO and General Foods transactions were â€Å"virtually† identical, except  that General Foods repurchased its stock over a period of time in the open market, whereas GEICO had made a â€Å"one-shot† tender offer. In the General Foods case we sold to the company, on each day that it repurchased shares, but left Berkshire’s ownership percentage unchanged. Maybe this difference triggered Peat Marwick to look back into the stock redemption, where they found discrepancies with the accounting treatments and recommended that Berkshire make adjustments to report the transactions appropriately. RECOMMENDATIONS/CONCLUSIONS After Berkshire’s 1984 audit, the company released Peat, Marwick, Mitchell & Company as its auditing firm. Berkshire reported that it was â€Å"dissatisfied† with Peat Marwick’s inconsistency regarding the proper accounting treatment for stock redemption. Corporate non-liquidating distributions to shareholders are usually treated as dividends income; however, distributions that qualify as stock redemptions are treated the same as a sale of stock by the investor to the investee. Therefore, capital gain treatment normally results. Corporate shareholders prefer stock redemptions to be treated as dividend income, because corporate shareholders received the benefits of the dividends, which are deductible and in most cases escape taxation. Qualifying stock redemption results in capital gains that are fully taxable at the corporation’s highest marginal rate. Warren Buffet employed the substance over form concept while accounting for Berkshire’s stock redemption transactions. Since the IRS considers proportionate redemptions to be equivalent to dividend distributions and are taxed accordingly, Buffet justified the accounting treatment used to record these truncations. References http://www.accountax.us/Taxation-%20Corporations%20Lecture%20V.pdf http://www.aicpa.org/Research/Standards/AuditAttest/DownloadableDocuments/AU-00314.pdf http://pcaobus.org/standards/auditing/pages/au508.aspx http://www.berkshirehathaway.com/letters/1984.html http://pcaobus.org/standards/auditing/pages/au316.aspx#au_316.52

A Family Systems Approach For Michelle Family - 1823 Words

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plot,setting, resolution, conflict, point of view,...

Creole Democracy I.Synopsis â€Å"Creole Democracy† is a clear presentation of one fundamental defect from of government. Democracy is based on the concept of the rule â€Å"of the people, by the people, for the people. â€Å"The success of a democratic form of government is based on the nature and condition of the electorate--- that they are literate enough to express their will in the ballot, that they have sufficient education to understand and analyze and decide on vital issues, and that they canimpose discipline on their emotions and themselves. To meet these requirements of democracy, Fambona tells us, most developing countries are still incapable. So the story ends in tragedy and death with the participants not really knowing it is all about.†¦show more content†¦Quick! Off to the mountains!† The vaquero didn t know that what he did was a crime as a sign of an uneducated man who just his leader: â€Å"Then it is true that this was a crime?† All that he thought was to kill t he other party with one reason at all. That he is an enemy. Realizing his mistake he turned himself to justice. Having regrets of his ignorance and still confused: â€Å"But weren t we supposed to conquer them? Weren t they our enemies? â€Å"The people of Camoruco are not yet ready for democratic changes. For them to have a successful democracy, the public and the electorates should be first educated about the meaning of democracy. The story proved that education of people and the leaders will only turn into chaos. The leaders should not think about themselves and be selfish but rather to put into mind that democracy is â€Å"of the people, by the people and for the people†. Each of the public should have a contribution for the success of the country not just merely being influenced by powerful leaders. The leaders of both party in the story don t have a clear goal of what they will do in their country, can t even notice the issues they are facing and discipline themselves rather all they want is to be in

Complementary And Alternative Pain Reduction - 1851 Words

Complementary and Alternative Pain Reduction Methods in Healthcare Grace Kavanah The University of Maine Complementary and Alternative Pain Reduction Methods in Healthcare Pain is the most commonly reported reason for coming to the hospital in America. It’s causes have a massive variance, and in many chronic cases the root source of pain can not be articulated at all. When a patient reports pain, the role of the nurse, and the whole healthcare staff, is to aim to reduce that pain. In many cases pain reduction can be attained through nonpharmacologic, complementary and alternative methods (CAM). Using CAM to reduce pain is an ideal scenario for both the patient and the healthcare staff as these alternative methods have fewer negative consequential effects. The following analysis will observe various methods of CAM pain reduction, highlighting two major CAM therapies of interest: music therapy, animal therapy. In addition, the following analysis will discuss how different demographics react to such therapies, with gender, age, ethnicity, and education level playing a role in relation to a patient’s willingness to be open to CAM. Lastly this analysis will discuss the drawbacks of CAM therapies in the medical community today, emphasising a lack of discussion between provider and patient, and the general lack of clinical education surrounding CAM therapies within the medical community. Major CAM Methods Music Therapy PhysicalShow MoreRelatedMassage Therapy As An Effective Alternative Treatment For Pain1581 Words   |  7 PagesMassage Therapy as an Effective Alternative Treatment in Palliative Hospice Care Amanda Oswald ABSTRACT The purpose of this review is to summarize research that indicates massage therapy as an effective therapeutic tool for pain relief, reduction of anxiety and symptom management for hospice patients. 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Cult of Thinness Free Essays

The author talks about the different ways in which the American popular culture, families, schools, peer groups, and the health and fitness industry undermine women’s self-confidence as they instill the notions that thinness is beauty and that a woman’s body is more important than her mind. She makes it known that there are many different factors as to why there is such a need to be thin these days and why there are so many eating disorders in our society. She blames the media as one of the leading contributing factors as to why our society is consumed with dieting, being thin, and body image and I agree with this. We will write a custom essay sample on Cult of Thinness or any similar topic only for you Order Now I believe that the media system is corrupt and it influences most of our perceptions, especially women. For example on magazine covers, there are usually pictures of women in bikinis, or even topless showing off their skinny bodies. And in beauty commercials, its usually skinny, tall women used to advertise beauty products. This images and frames are what is branded by media and society as â€Å"looking good† or â€Å"being sexy†; as a result of this, women especially adolescents and young adults compare themselves to these models and feel inadequate. They feel like that is how they are meant to look and may end up dieting or starving themselves or even in more tragic consequences undergo surgery. A 12 year old girl stated, â€Å"When I see those twigs of people in the magazines and on TV, I say, â€Å"I’m going to go on a diet. † You almost want to get thin just so you can wear the right clothes. I watch all my junior high friends – they look like something out of a magazine†. However, the author also talks about some cultures that think that voluptuous, curvy women are a sign of prosperity and also an indicator of their ability to cook and take care of their family How to cite Cult of Thinness, Essay examples

Stock Evaluation Woolworths Limited

Question:rnDiscuss about theStock Evaluationfor Woolworths Limited.rnrnAnswer:rnrnIntroductionrnThe firm that has been used for this stock valuation task is Woolworths Limited which deals with organised retail business with the predominant format being that of supermarkets. The company enjoys a healthy share of around 40% and together with Coles form a virtual duopoly which in the recent years has been challenged to some extent by the entrance of German discount retailers like Aldi. The company besides being present in the grocery and liquor business also has major presence in fuel retailing (in association with Caltex), runs discount department stores, has presence in the home improvement segment besides hotels. The major market served by the company is Australia which accounts for more than 85% of the revenue generated. The company has presence in wide parts of Australia with estimated store strength of about 975 stores and is steadily increasing its presence and market share in th e New Zealand market. The company also has limited presence in selective verticals in South Africa, Hong Kong, India and UK (Woolworths, 2016). The current market capitalisation of the firm is $ 30.77 billion. The given report aims to conduct a quantitative and qualitative analysis of the company taking into consideration the last five year financial statements so as to opine on whether investment should be made in the stock or not.rnRecent Stock MovementrnThe stock price movement of Woolworths during the last one year is captured in the graph shown below (Yahoo Finance, 2016).rnIt is apparent from the above that in the last one year, the stock has delivered negative returns and has underperformed the ASX 200 index. Further, it is also apparent that there is a range bound movement of the stock with support coming in at lower levels and resistance at the higher value of the stock as investors book profits (Geurard, 2013). Considering the competitive nature of the industry and the cur rent macroeconomic conditions that are not ideal for the industry, such kinds of sideways movements are not unexpected. Further, even though the fundamentals of the company remain in place, it seems that the stock is poised to underperform the broader markets primarily on account of industry dynamics, lower fuel prices and lacklustre trading environment (Petty et, al., 2015).rnQuantitative FactorsrnThe impact of various quantitative factors include the trend analysis with regards to the major items in the financial statements namely the income statement and balance sheet along with analysis of selected ratios so as to comment on the financial performance of the firm. The concerned period of interest is from FY2012 FY2016 which constitutes a period of five years.rnrnIncome Statement ItemsrnRevenuernThe revenue growth for the company has been impressive in FY2013 as compared to FY2012 on the back of improved trading environment coupled with rising consumer confidence and increased pri ces of fuel. After a uptrend from FY2012 to FY2014, there has been a negative growth or de-growth witnessed in the revenue in FY2015 and FY2016. The negative growth in these years may be attributed to namely two years i.e. increased competition especially with the entry of international German discount retailers which have increased their market share coupled with sharp decrease in the fuel prices which has adversely impacted the fuel sales. Further, in FY2015, there has been decrease in the number of Caltex outlets which have been added to the revenues and hence the revenue has been lower (Woolworths, 2012; 2014; 2016).rnGross ProfitrnFrom FY2012 to FY2014, there is an increasing trend in the gross profit which has increased from $ 14.46 billion to $ 16.48 billion. The encouraging trend in this regard is the improvement of gross profit margins by 54 bps and 17 bps in FY2013 and FY2014 respectively. The improvement is primarily driven by expanding margins in the Australian food and liquor business coupled with Hotels. Besides, in FY2014, the gross profits were negatively impacted by the decreasing margins in the general merchandise business. However, during FY2015 and FY2016, there have been shrinking gross profit margins which are attributable to the lower prices of fuel coupled with higher competition in the food and liquor segment which is stalling price increases and thus in order to stem the falling market share, the margins have fallen (Woolworths, 2012; 2014; 2016).rnNet Financing CostsrnWith regards to financing costs, there has been an increase trend in this regard from FY2012 to FY2016 which has been briefly interrupted in FY2014 as there has been a slight decrease in the finance costs on the back of stellar performance in FY2013 on the basis of which there has been a reduction in the outstanding debt and hence leading to the decreased expense in the form of finance costs. Additionally, some part of the total interest costs in the various years is al so capitalised which influences the overall financing costs (Woolworths, 2012; 2014; 2016).rnNet ProfitrnWith regards to net profit, there has been an increasing trend from FY2012 to FY2014 but the same has been reversed in the subsequent years and infact in FY2016 the company has reported a loss. While the decrease in FY2015 net profit may be explained on account of lower gross profit margins coupled with increased operational costs, but the losses made in FY2016 can be explained on the basis of loss to the extent of $ 3.1 billion on account of discontinued business (Hydrox Holdings Pty Ltd). Further, there has been a steep rise in the administrative expense by about 21% on a y-o-y basis which has led to steep fall in the operating margins of the continued business operations (Woolworths, 2012; 2014; 2016).rnrnBalance Sheet ItemsrnCashrnFrom FY2012 to FY2015, there is an uptrend with relation to the cash balance which has come down only in FY2016. While during FY2012 to FY2014, the re has not been much change in cash balance, however the FY2015 cash balance is significantly greater than FY2014 corresponding figure which is caused due to lower cash flow on amount of investing due to a weak trading environment persisting in Australia. However, the lower cash balance in FY2016 is primarily attributed to the lower cash flow from operations which have led to decrease in the overall cash balance (Woolworths, 2012; 2014; 2016).rnIntangible AssetsrnWith regards to intangible assets, there has been an increasing trend from FY2012 to FY2014 which has then reversed into a declining trend over the period FY2015 FY2016. While, the decline in FY2015 is only marginal and caused due to discontinued business, the decline in FY2016 is comparatively more significant and prompted by the decline in goodwill to the tune of $350.9 million and this decrease has been witnessed in relation to the continued operations only(Woolworths, 2012; 2014; 2016).rnTrade and Other PayablesrnThere is an increasing trend in the trade and other payables which is witnessed during the given period i.e. FY2012 FY2016. This is apparent from the fact that trade and other payables have increased from $ 5.24 billion as on June 30, 2012 to $ 6.26 billion as on June 30, 2016. It is apparent that the increase of trade payables reflects towards a greater credit period for the company which to an extent may be driven by the difficult conditions in the retail industry and hence the company would want to minimise the working capital requirements (Woolworths, 2012; 2014; 2016).rnNon-Current BorrowingsrnIn relation to the non-current borrowings, there is a declining trend from FY2012 to FY2015 but has increased only in FY2016. The increase in FY2016 is primarily on account of increase in long term bank loan to the tune of $ 853.2 million. The decrease in the long term borrowings augers well for the company and ensure that the company has less leverage and therefore could raise more debt to wit hstand the competitive environment using deep financial pockets (Woolworths, 2012; 2014; 2016).rnrnShareholders EquityrnThere is an increased equity trend from FY2012 to FY2015 primarily due to increase in issued capital and higher retained earnings on the basis of the profitable operations of the company. The issued capital has seen an incline in every year of the given period including FY2016. As a result of this, the issued share capital has increased from $ 4.37 billion at the end of FY2012 to $ 5.35 billion at the end of FY2016. This highlights that during the period under assessment incremental shares to the tune of $ 0.98 billion have been issued by the company. However, the major increase in equity is on account of increased retained earnings. The decline in equity as on June 30, 2016 could be explained on the basis of sizable reduction in the retained earnings due to loss of $ 3.1 billion incurred due to discontinued business as explained above (Woolworths, 2012; 2014; 2016 ).rnThe selective ratios for the company for the given time period are computed as follows (Woolworths, 2012; 2014; 2016).rnrnrnrnrnParticularsrnrnrn2012rnrnrn2013rnrnrn2014rnrnrn2015rnrnrn2016rnrnrnrnrnReturn on total assetsrnrnrn8.42%rnrnrn10.15%rnrnrn10.13%rnrnrn8.47%rnrnrn-5.25%rnrnrnrnrnNet profit marginrnrnrn3.29%rnrnrn3.85%rnrnrn4.02%rnrnrn3.64%rnrnrn-2.12%rnrnrnrnrnInventory Turnoverrnrnrn11.0rnrnrn10.2rnrnrn9.5rnrnrn8.8rnrnrn9.4rnrnrnrnrnCurrent ratiornrnrn0.9rnrnrn0.9rnrnrn0.9rnrnrn0.8rnrnrn0.8rnrnrnrnrnPrice earnings ratiornrnrn17.93rnrnrn18.05rnrnrn18.01rnrnrn15.83rnrnrn-21.38rnrnrnrnrnDebt ratiornrnrn0.61rnrnrn0.58rnrnrn0.57rnrnrn0.56rnrnrn0.63rnrnrnrnrnThe explanation with regards to the above ratios is offered below.rnROA or Return on Total Assets The ROA has jumped from 8.42% in FY2012 to 10.15% in FY2013 primarily on account of higher percentage increase in net profits as compared to the total asset increase. However, there was a marginal decline in ROA in FY2014 o ver the previous year as the profit increase was marginal and not able to match the percentage increase in total assets. But the real worry is the decline in FY2015 and FY2016. There is a drop in ROA in FY2015 due to the drop in profitability of business operations caused to falling margins of fuel retailing besides higher competition experienced in the food and liquor segment leading to negative growth in revenues. Besides, in FY2016, the company incurs a loss due to discontinued operations which leads to a negative ROA (Woolworths, 2012; 2014; 2016).rnNet Profit Margin There has been a positive trend in the net profit margin during the period FY2012-FY2014 on the back of growing margins in the food and liquor segment coupled with hotels business. This is the result of various initiatives undertaken by the company to streamline the operations and cut down on the overheads costs so as to ensure that the company stays competitive in a market highly sensitive to prices. However, the net profit margins have taken a dip in FY2015 primarily on the back of lower gross profit margins as the competition level increased coupled with higher operational expenses. The decline in margins in FY2016 from continued businesses is on account almost 21% increase in the administrative costs over the corresponding values in FY2014. Further, the discontinued business loss to the tune of $ 3.1 billion has resulted in the PAT turning negative (Woolworths, 2012; 2014; 2016).rnInventory Turnover There is a declining trend in the inventory turnover from FY2012 to FY2015 which hints at higher cash cycle and is not in the best interest of the company or the shareholders. This may be attributed to the continuously rising inventory levels from $ 3.7 billion as on June 30, 2012 to $ 4.87 billion as on June 30, 2015. This may be reflective of the muted sales of the company which may not be in accordance with the expectations of the company. However, at the end of FY2016, there is a decline in the inventory level and hence an improvement in the inventory turnover (Woolworths, 2012; 2014; 2016).rnCurrent Ratio The current ratio for the company has shown very slight variation as from FY2012 to FY2014, the current ratio remains almost constant at 0.9. This may be attributed to proportionate changes in both current assets and current liabilities. However, in FY2015, there is a decrease in the current ratio fuelled by the higher percentage increase in the current liabilities caused due to increased amount of current borrowing in FY2015 as compared to the previous year. In FY2016, even though there is a decrease in current borrowing by almost $ 1.1 billion, but to some extent this is balanced by increase in $ 0.8 billion on account of provisions, the net result of which is that the current ratio has not improved (Woolworths, 2012; 2014; 2016).rnPrice earnings ratio With regards to P/E ratio, there is a slight improvement from FY2012 to FY2013 which may be on account on bet ter financial performance by the company. However, for FY2014, the P/E ratio remained almost static. Then, in FY2015, due to increased competition and falling margins especially on fuel retailing, the P/E ratio was adversely impacted particularly on concerns with regards to growth especially in the short term. The concern continued in FY2016 as earnings became negative on the back of loss to the tune of $ 3.1 billion arising from discontinued business (Woolworths, 2012; 2014; 2016).rnDebt Ratio The debt ratio has shown a marginal declining trend from FY2012 to FY2015 but there has been a reversal in the trend in FY2016. The declining value of debt ratio was favourable for the company implying that the liability as a percentage of debt was on the decline. The increase of the debt ratio in FY2016 is primarily on account of the decrease in total assets brought about mainly in decrease of PPE from $ 10.06 billion as on June 30, 2015 to $ 8.26 billion as on June 30, 2016. This has been brought about due to the discontinued business (Woolworths, 2012; 2014; 2016).rnrnIndustry Comparison and RecommendationrnStrengths of the companyrnrnThe ROA of the company for all the given years (on basis on continuing operations) is greater than the industry average of 1.88%.rnThe current ratio of the company is marginally better than the industry average of 0.88 for FY2012 to FY2014.rnThe net profit margin and debt ratio of the company is also superior to the level of the industry.rnPosition of being market leader with a sizable market share.rnrnWeakness of the companyrnrnThe company needs to improve with regards to short term liquidity particularly considering the competitive landscape of the industry.rnThe overall competitive nature of organised retail industry in Australia.rnThe e-retailing segment of the company lacks strength.rnThe macroeconomic conditions associated are not favourable at the present.rnrnFrom the above, it is apparent that the company in the long run would deliver returns as the business fundamentals remain sound. But in the near to medium term, the stock is expected to be range bound only as the margins made witness more pressure and thus have a downward bias. Clearly, it is best to avoid the retail industry stocks and instead look at companies in other industry segments which offer much better value and growth upside. Hence, taking above factors into consideration, it may be recommended that investment should not be done in the companys stock (Parrino Kidwell, 2011).rnStock Valuation ExercisernDividend paid by Woolworths in FY2016 ($ per share) = $ 1.65717rnPerpetual dividend growth rate (given) = 4% p.a.rnExpected return on Woolworths stock = 9% p.a.rnHence, expected dividend in FY2017($ per share) = 1.6517*1.04 = $ 1.72345rnThus, by applying the Gordon Dividend Discount Model, we get (Northington, 2011)rnFair price of the stock = 1.72345/(0.09-0.04) = $ 34.47rnThus, at current price, the stocks seem to be underpriced. However, it is imperative to note that market dynamics tend to function differently from theoretical prices and it may take a long time before this aberration is corrected as the markets may not be efficient (Kane Marcus, 2013).rnrnReferencesrnGuerard, J 2013,Introduction to financial forecasting in investment analysis, 6th eds., Springer, New YorkrnKane, BZ Marcus, AJ 2013, Essentials of Investment, 9th eds., McGraw-Hill International, SingaporernNorthington, S 2011, Finance, 6th eds., Ferguson, New YorkrnParrino, R Kidwell, D 2011, Fundamentals of Corporate Finance, 3rd eds., Wiley Publications, LondonrnPetty, JW, Titman, S, Keown, AJ, Martin, P, Martin JD Burrow, M 2015, Financial Management: Principles and Applications, 6th eds., Pearson Australia, SydneyrnWoolworths 2012, Financial Report 2012, Woolworths Website, Available online from https://www.woolworthslimited.com.au/annualreport/2012/pdf/WW_AR12_FinReport.pdfrn(Accessed on October 11, 2016)rnWoolworths 2014, Annual Report 2014, Woolworths Website, Available online from https://www.woolworthslimited.com.au/annualreport/2014/files/Woolworths_Annual_Report_2014.pdf (Accessed on October 11, 2016)rnWoolworths 2016, Annual Report 2016, Woolworths Website, Available online from https://www.woolworthslimited.com.au/icms_docs/185841_Annual_Report_2016.pdf (Accessed on October 11, 2016)rnYahoo Finance 2016, Woolworths Summary, Yahoo Finance Australia, Available online from https://au.finance.yahoo.com/q?s=WOW.AX (Accessed on October 11, 2016)rnrn