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

Genogram from a Family Systems Approach for Michelle Family The most fundamental of a family is interaction. The interconnectedness among family members help to maintain a family structure. According to McGoldrick (2006), family patterns repeat from one generation to the next generation. These triangular patterns are impacting functioning, relationships, and family structure. Looking at the current and historical context of the family, the genogram illustrated some repetitive patterns in Michelle’s family. There are many intergenerational losses and lack of connections among the family members. The unresolved mourning can be traced to the generation of David’s parents. Starting from the generation of David’s parents, there were a few losses, such as miscarriage or potentially stillbirth. It is likely that David’s parents were grieving over the loss of his brother, therefore David was named after his elder brother. This may be a form of remembrance or he may be a replacement child of his elder brother. It is also likely that David’s mother; Edith did not have the space for grieving over her miscarriages that contributed to her having an affair with their best friend, Bob. At the same time, it is also likely that David’s father was sharing the same emotions as Edith. Consequently, when he lost his children and best friend, he turned to alcohol for coping. Apart from experiencing losses of siblings at a younger age, David lost his parents and wife when he is aShow MoreRelatedThe Amazing Flexible You Is A Social Thinking Curriculum For Preschool And Early Elementary Years852 Words   |  4 Pagesyears. It was adapted from Michelle Garcia’s Social Thinking curriculum that provides an interactive tool kit. The program introduces the concepts of: Thinking Thoughts and Feeling Feelings, The Group Plan, Thinking with Your Eyes, Body in the Group, and Whole Body Listening. 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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