Apply for Mount Saint Vincent University for master of education Essay

Apply for Mount Saint Vincent University for master of education - Essay Example Most of the studies have indicated that every individual that receives the opportunity to study, experiences a learning process of around 14 to 18 years, depending on the education system of every country. Subsequently, such an individual is considered good enough to perform rightly and efficiently in his/her professional life. However, recent researches and studies have initiated a new and innovative concept of lifelong learning, which motivates and encourages individuals to continue the process of learning throughout their lives. A limited process of learning of 14 to 18 years is not considered effective enough to facilitate individuals throughout their lives. In other words, the concept of learning has been broadened in terms of its duration, as well as, attitude, which will allow individuals, as well as, societies to enrich through new ideas, discussion, and dialogues in an intellectual and interactive manner. (Holmes, pp. 23-25) In terms of academic background, I have received my undergraduate degree from King Khalid University, Saudi Arabia. My passion for learning and enthusiasm for enrichment of emotional maturity has resulted in application at one of the reputable educational institutions, Mount Saint Vincent University in Halifax, Canada. In specific, I am interested to attain the Masters Degree in Lifelong Learning, as I have been able to attain tremendous respect for this concept of learning after its detailed analysis, as earlier mentioned in the paper. One of the significant characteristics of Lifelong learning is that it offers a combination of pedagogical and andragogical perspective of learning by the provision of teacher-focused education with amalgamation of a broader perception of learning through focusing learners from all age groups, sects, races, and academic background. (Harrison, pp. 42-43) In specific, Lifelong learning offers

Research methods and Skills Essay Example | Topics and Well Written Essays - 1000 words

Research methods and Skills - Essay Example been found to leach from plastic products, more so in high temperatures and basic or acidic conditions, such as during autoclaving.2 This becomes more alarming with the pressing problem of global warming.3 Food is also considered the most significant source of BPA exposure worldwide. In fact, BPA has already been detected in almost all of urine samples collected from USA.4 When BPA is imbibed, it is metabolized by the liver into BPA glucuronide, which is excreted through the urine.5 BPA is an estrogenic monomer that binds weakly to nuclear estrogen receptors. In fact, its binding to estrogen receptors is 1000 – 10, 000-fold lower than the natural hormone E2.6 Currently, it is now polymerized to make polycarbonate plastic, which is now extensively used in the manufacture of food and beverage cans and dental materials. The potency of BPA partly results from the low dose needed to produce a physiologic response. This is because the activation of the effector is longer than the actual hormone-receptor binding, or the number of receptors is greater than the number of molecules. Thus, despite the low affinity of BPA to the receptor, low concentrations still initiate a response. In fact, the linear concentration between receptor occupancy and hormone concentration is preserved only up to 10% receptor occupancy. Above this, saturation of response occurs first, and saturation of receptor follows.7 BPA mimics the activity of 17ÃŽ ²-estradiol, posing a strong estrogenic activity. With just 10 – 20 nM, it was seen to competitively bind to estrogen receptors, proliferation of MCF-7 breast cancer cells, induction of progesterone receptors, and reversal estrogen action by tamoxifen. It induces proliferative and stimulatory changes in estrogen targets.8 There is a major concern to public health due to its high potential for human exposure and to its demonstrated toxicity (endocrine disruptor effect). A growing number of health experts and consumers are becoming concerned

Influencing Individuals and Groups Essay Example | Topics and Well Written Essays - 750 words - 1

Influencing Individuals and Groups - Essay Example Negotiation is then sought, to amicably discuss and assess the situation and to find solutions to the problems incurred. In order to combat this, effective leadership is needed. Leaders become role models for people and help them to achieve goals. Wal Mart needs to resolve issues by finding feasible solutions for conflicts. Employees who have a positive attitude are a boon to an organization, and, it is easier to retain and train those employees rather than to try and modify those with a negative attitude. As conflict resolution needs participaton and collaboration of employees; Wal Mart helps in bringing about people development, collaboration and team work among its employees. School Press, H. 2006. Written Communications that Inform and Influence: The Results-Driven Manager Series (Paperback). Harvard Business School Press Books, 1. Retrieved from Business Source Complete

A divided America on the topic of abortion Essay Example for Free

A divided America on the topic of abortion Essay Abortion In modern history, there have been few subjects of political and social interest as divisive as that of abortion. Ideologically, many traditional religions such as Christianity have stipulated that abortion itself is an unethical practice and one that is morally wrong. Many Christians assert that there is some divinely unethical nature of the mishandling of the fetus itself. Most arguments of this kind essentially pertain to the status of the fetus as a person, one that has the right to the same advantages and privileges as its human mother. As such, abortion has come to dominate many discussions and people have found platforms to argue for or against the acceptance of abortion as a norm in our society. Much of the opposition surrounding the ethics of abortion pertains to religious belief, and many ascribe to the notion that abortion contradicts divine command theory. As such, there are many factors to consider in interpreting abortion from a theological standpoint, as well as in addressing the positives and negatives associated with the act itself. When the United States first began establishing itself as its own country, many of the states simply transferred English laws to their own and used these as a sort of template for how to conduct their own affairs. Abortion was handled much the same in this way, and the structure for how many states began to approach abortion came from how they chose to handle it within this framework. Many states essentially stated that it was not allowed or permitted after around the 15-20 week period immediately following conception. Anti-abortion laws and statutes officially began to manifest themselves in the United States around the 1820s, and these laws expanded upon previous laws to help supplant the notion that abortion was unethical. In the year 1821, one of the first prominent anti-abortion laws came forth from Connecticut, which outlawed medicines that were given to women to help further abortions. In 1829, New York made abortions that Despite the advances that were occurring in medical science and the developments in these fields, many people in the United States still considered it an unethical dilemma to condone the acts that were associated with abortion, or to facilitate them. As medical sciences grew in support of the belief that fetuses didnt exhibit the same traits or characteristics as fully-born children, many theological centers and individuals began imposing their own opinions of the matter, to stand in stark contradiction to these claims. Scientists in this era concluded that conception was merely an inauguration point for the development of a fetus and that it was a continuous process of development until the child fully possessed all of its human-like traits and characteristics. Criminalization of abortion became a huge trend in the late 1860s, as various doctors and legislators began doubling down on the act and making it illegal. By the year 1900, abortion had become a felony in essentially every s tate in the country. Yet, some states had included clauses or provisions which were meant to ensure that abortions could be conducted in a limited nature, when issues such as the health of the mother became a factor, or if the pregnancy was the direct result of incest or rape. In 1973, the Supreme Court was a group the case of Roe v. Wade, one that would transform the history of abortions in the country and provide a catalyst for a more in-depth examination of the ethical nature of abortions themselves. In this particular case, the Supreme Court came to rule that a statute in Texas which forbade abortion, except when it was necessary to ensure the safety of the mother, was unconstitutional. This decision sparked a tremendous amount of backlash and controversy and has provided a plethora of individuals and groups with a reason to once again oppose the act. Many of these groups and entities have debated on the ethical nature of abortion, and have used the divine command theory to support their claims. The divine command theory is a theological approach to understanding and interpreting the grounds of morality, as well as establishing what is moral and what is not. Unlike the ethics of natural law, the divine command theory is used to establish a clear and present moral direction, and to help supplant a sense of duty and ethical foundation. The theory is developed on the notion that God is the creator of the world, and that the laws which govern morality and ethics are extensions of the commands that God asserts. Furthermore, the argument among many theological representatives is that God would be against the nature of abortion, as it stands contrary to the Commandments that God gave humans. A direct and implicit interpretation of the morality of abortion may be surmised from the scripture in Exodus 21:22-24, in which the scripture itself discusses a woman who has a miscarriage as a result of two men who are fighting in the passage. (The Bible, Exodus 21:22-24) The scripture does n ot directly state that she had an abortion at that moment, but it does provide an inference into the miscarriage and states that it was immoral due to the fact a life was lost in this time. As such, it has become a principle Christian belief that a life of a fetus is equivalent to that of an adult human, in terms of the value that God places upon it. In the passage 44:2, it is stated that â€Å"thus says the Lord who made you and formed you from the womb, who will help you. Do not fear, O Jacob My servant, and you Jeshurun whom I have chosen.† (The Bible, Isaiah 44:2) In this bit of scripture, God consults with Jacob and tells him that he should not have any fear because God provided him with life directly from the womb of his mother, which would imply that God has established some level of plan or purpose for Jacob even when he was a fetus. It is this basis that many have used to establish their interpretation of divine command theory. This notion supports the centralized argument that it is humanitys responsibility to provide the most maximum safety for that of all human life, which these theorists argue starts in the womb and immediately after conception. The moral ramifications of abortion, as this theory postulates, is that God will not condone actions which facilitate the likelihood of abortion or the helping of abor tion in any way. While it can be said that the religious groups believe that the life of a fetus is sacred, many people outside of these mentalities believe that there is an inherent right in the mother to control what she does with her own body, and how she goes about doing it. Many of these individuals argue that their belief systems do not correlate directly with this mentality and that it is unethical in itself to subject a woman to the harsh realities of being a mother if it was never her intention to become a mother in the first place. As such, it is worth understanding abortion itself and what it can entail, to better interpret the ethical nature of the act and which side presents a more sound argument. Abortion can be a tremendously devastating act, psychologically. A study that was amassed from approximately 56,000 public records in California concluded that women who had abortions were 160 percent more likely to be sent to the hospital for psychiatric care, as opposed to women who had chosen to see the pregnancy through and deliver the child. (Barlett, 2004, 729) Furthermore, it was noted that the rates of treatment for psychiatric issues were higher by a large margin for upwards of four years, in women who had abortions. Further studies indicate that many women experience psychological issues as early as eight weeks after they have an abortion. These studies have found that approximately 44 percent of women have some level of nervous disorder and that 36 percent note that they have some level of disturbance in their sleep patterns and in their overall regular sleep cycles. (Barlett, 2004, 731) Over 30 percent of these women also note that they openly regret the decision that the y made, and approximately 11 percent of people are prescribed some type of medication to help them cope with the stresses associated with their decision. (Barlett, 2004, 731)   Women who have abortions are more prone to visit psychiatrists than those who have delivered children to full term. Researchers have concluded that there is only one real positive emotion that is correlated with abortions, being that of relief. Yet, this can quickly be supplanted by feelings of numbness or a sense of emotional paralysis. It is often the case that women who have abortions are left with a general inability to express their emotions after the procedure, correlating whatever feelings they have to just a general appreciation for having been able to survive the procedure, with little more being reported. This can lead to a more stable, concurrent level of negative reactions which can continue to manifest themselves throughout the next several months following an abortion-related procedure. Significant studies have concluded that approximately 50 percent of women question their decisions after the procedure, and over 55 percent express some sort of guilt within the 8 weeks that follow the abortion. (Barlett, 2004, 735) Furthermore, approximately forty percent of women who abort report to having sexual complications or dysfunctions, which can last for a short or long period of time in most cases. These can include increased pain or a loss of pleasure from the acts of sex and an aversion to the genitals of their partners, or to males in general. Psychological issues arent the only ones that can manifest themselves after an abortion. Approximately one hundred complications have been associated with the induction of abortion, and all of these have the capacity to affect the women undergoing these processes. Statistics on abortion state that 10 percent of women who are undergoing some type of abortion-related procedure have some type of immediate physical or mental issue that occurs during or after the process and 20 percent of these can be seen as major factors and health-related issues. (Barlett, 2004, 737) Among many of the complications that can physically happen are infections, fevers, abdominal pain, bleeding, vomiting and intestinal disturbances. The most commonly identified major issues that can happen are serious infections, embolism, convulsions, cervical injury, hemorrhaging, perforation of the uterus, bleeding, and shock during the process. A study which cataloged the effects of 1,180 abortions concluded that over 2 7 percent of the patients had some type of infection that lasted more than 3 days after the process. (Barlett, 2004, 741) While it can be said that many of these issues can be immediately treated, a large percentage of them can lead to long-term, more serious results and damages to the reproductive system and other attributes of the womans body and health. 3 to 5 percent of women who have aborted are accidentally left sterile as a result of the effects of the process, and this is even greater when venereal diseases are introduced into the equation. (Barlett, 2004, 740) Despite these factors, there are many potential ethical positives to abortions. Regardless of the health risks associated with abortion, it should ultimately be left to the woman to decide what she will do with her own body. Many experts argue that pregnancies should not be enforced upon the acts of sex. In 2008, a study concluded that 41 percent of all pregnancies that happened in the United States were not planned, or indirectly accidental in some way. (Finn, Moore, 2008, 112) When one considers the size of the population in the United States, there are over 85 million women who identify with this claim. The number of reasons that a woman should be able to cancel a pregnancy should not be so limited, and this affects a large percentage of the population in the United States. Delineating these decisions and the freedom for a woman to have her own say over her body does not pose a significant level of intrinsic value in the life of the woman. Furthermore, the issue becomes more complex when one looks at the availability of contraception. It is often the case that many women who have sex and their partners are not able to readily find contraception, nor do they have the means to ascertain it themselves. Since 1980, there has been a 61 percent decrease in the funds that are available through the Title X program, which helps to provide affordable services to people to help them dictate their family planning. (Finn, Moore, 2008, 110)   Many socially-charged issues and the dissemination of anti-abortion materials have catalyzed a scenario in which women do not have the proper access to the resources that they often need to ensure that they do not get pregnant. When this is considered, enforcing abortions does not have much of an ethical foundation in itself, supplanting the notion that womens bodies and their decisions are not valid or hold the same level of importance as the livelihood of fetuses. Abortion is a tremendously important social issue, and one that has manifested itself in many different ways throughout the course of modern American history. Many opponents of abortion believe that the act is against Gods will, and that God has ordained the value of a fetus existence as comparable to the lives of humans. This coincides with the principles of divine command theory according to many of these individuals, and their belief system is built around the notion that abortion is a fundamentally unethical issue to God. Many ideologies have used this as a principle justification for their unwillingness to understand or accept abortion, which has led to a significant level of controversy in the United States between the groups of people who oppose it and those who support it. As a result, the United States has had a turbulent history with the subject of abortion, which has led to much debate in terms of a womans right to her own livelihood and body. While it can be said that abo rtion can be a potentially harmful action in terms of the effects it can have psychologically and physically, a woman should still be given the freedom to choose how she goes about her own body, and what she chooses to do with it. Socially, it is the responsibility of a nation such as the United States to provide the most adequate resources that it can to help facilitate these processes and the decisions that women make. References Bartlett, LA. Risk factors for legal induced abortion-related mortality in the United   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   States.Obstet Gynecol.Oxford: Oxford University Press. 2004. p. 729-745. Finer, Lawrence B.;   Moore, Ann M.   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   Reasons U.S. Women Have Abortions: Quantitative and   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   Qualitative Perspectives Perspectives on Sexual and Reproductive Health. 2008. pp..   Ã‚  Ã‚  Ã‚  Ã‚   110–128. The Bible: Contemporary English Version, 2000. London: Harper Collins. Weingarten, Karen. Abortion in the American Imagination: Before Life and Choice, 1880-1940,   Ã‚  Ã‚   2000.New Brunswick, NJ: Rutgers University Press. p. 176.

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.

Appearance vs Reality Essay -- essays papers

Appearance vs Reality One normally disguises in order to be someone else, whether this be in a costume during Halloween, or as a character in a play or movie. Shakespeare uses the idea of disguise in his ‘Taming of the Shrew’ The minor theme of the play is appearance vs reality. Throughout the drama, things are never really as they seem. Katherine appears to be a real shrew, but it is all a cover-up for the hurt she feels. Bianca appears to be a self-sacrificing angel, but she is really a spoiled young lady who can quickly revert to shrewish behavior. Baptista appears to the outside world as a wonderful father; in truth, he pampers Bianca, totally spoiling her, and treats Katherine badly, depriving her of the loving attention she needs and seeks. Pe...

Clarkson Lumber Case Study

CLARKSON LUMBER CASE STUDY B RADY CLIFFORD †¢ DAN HORTON †¢ EMIL HYMAS Y †¢ RICH WILKINSON EXECUTIVE SUMMARY Clarkson Lumber Company, owned by Mr. Keith Clarkson, has been in business for 15 years and currently has 15 employees. Firms who have worked with Clarkson speak very highly of him, saying that he is conservative and his operating expenses are low. The company’s revenues are projected to continue to grow. Recently, Clarkson Lumber’s accounts payable and notes payable have increased significantly.The company has not been able to take advantage of trade discounts in recent years because of lack of funds and because of investments due to the company’s growth. While Clarkson Lumber has been increasingly profitable in recent years, the company has found the need for additional financing. Clarkson’s current bank will not provide more than $399,000 in financing without a personal guarantee. Clarkson is hoping to secure more financing in orde r to improve profitability by taking full advantage of trade discounts. The company is working with Northrup National Bank to possibly secure a larger loan; up to $750,000.Northrup’s credit department is currently investigating Clarkson Lumber to see if the firm qualifies for this additional financing. Our team has identified several key issues with Clarkson Lumber’s current financial situation. The company’s over-arching financial issue is cash flow. Clarkson is borrowing too much to make up for a cash flow shortage. Clarkson’s accounts receivable is increasing and the company is still using a 2% accounts payable discount, which is contributing to the lack of available cash. The cash flow that the company does have is being used inefficiently as the sources of cash comes from financing.Thus, Clarkson Lumber is growing at an unsustainable rate and is too reliant on short-term financing. Even if Clarkson receives the $750,000 from Northrup, the company wil l eventually be bankrupt if it does not curtail its growth rate. We recommend that the company utilize more long-term debt instead of short-term debt. Long-term financing will require smaller payments at lower interest rates, which will increase CLARKSON LUMBER CASE STUDY – FINAN 6022-002 †¢ PAGE 1 Clarkson’s cash flow. Clarkson may benefit from reducing inventory by increasing sales or reducing inventory growth.Another option would be to lower costs by negotiating cheaper prices with suppliers. Both options will increase the company’s cash flow. Finally, we recommend increasing accounts receivable turnover. With an increase in account receivable turnover, Clarkson will experience quicker collections and will not have to pay as much in finance charges, again leading to additional cash flow. ANALYSIS The approval process for the loan from Northrup National Bank, required that investigators be sent to research Mr. Clarkson and his company. The investigation p ointed out a few important financial aspects of the company that are worth mentioning.In 1994, Mr. Clarkson bought out the other company partner for $200,000. This amount was to be paid off in 1995 and 1996 using semi-annual payments at an interest rate of 11%. From 1993 to 1995, net sales volume for CLC has increased from 2. 9 million to just over 4. 5 million. After yield profits for the same years also increase from $60,000 in 1993 to $77,000 in 1995 (see Exhibit 1). The investigation also paid special attention the debt position and current ratio of CLC. It was reported that sales are expected to reach $5. 5 million in 1996 and could be more if the prices of lumber rise.Despite these profits, there was a shortage in cash which lead to an increase in borrowing. In order to stay within the borrowing limits set by Suburban Nation Bank, a lot of borrowing was being done through trade credits. In 1995 and 1996 this trade debt was rapidly increasing and was creating some concern. If t he market is struggling then trade credit is normally not recommended; however, for CLC the trade credit was a short fix for long term problem. Even with the growing trade debt, CLC still was comparable to the overall percentages of other lumber outlets (see Exhibit 3).It is also important to recognize specific ratios related to the company. The current ratio, which is helpful in understanding asset liquidity or inefficient use of cash flow, decreased from 2. 5 in 1993 to 1. 1 in 1995. High-profit companies have a current CLARKSON LUMBER CASE STUDY – FINAN 6022-002 †¢ PAGE 2 ratio of 2. 52. ROE for Clarkson Lumber remains relatively steady; it increased from 1993 to 1994 but decreased to 17. 1% in 1995. This ROE is only slightly lower than the ROE for high-profit companies which is at 22. 1%. After reviewing Clarkson Lumber’s financial situation, several key issues became apparent.First, the company is clearly growing at an unsustainable rate. Exhibit 3 (various s tatistical ratios), shows the average internal growth rate of the company at 6. 06% and the average sustainable growth rate at 15. 78%. However, over the three full years analyzed, the company has an average growth margin of 24. 5% and an average asset growth margin of 33. 69%. This continues in the forecasted 1996 year as the company is projected to increase revenue by roughly 21. 7%. At the company’s current level, it cannot continue to support its current growth rate going forward and will require more debt to finance this growth.Therefore, the company seems to be overly reliant on short term financing for its operations. As seen in Exhibit 5, the company projects to have $5. 5M, with most other accounts are based on the historical averages. Exhibit 5 also shows that Clarkson would need between $971K or $696K of external financing. Another issue found dealt with the company’s cash flow (see Exhibit 4). When the company generates net income, it is immediately engulfe d in two areas: the increase in accounts receivable, which increased from $306K to $411K to $606K from 1993 to 1995, and inventory, which also increased from $337K to $432K to $587K during those years.Due to these increases, and despite rising the liability accounts of notes payable from trade and accrued expenses, the company had negative cash flow from operations and needed external financing to purchase its fixed assets and pay down the debt they already had (again see Exhibit 4). Although having negative cash flows from operations is not necessarily bad in the short run, if this trend continues, it provides no long term benefit for the company. Thus, we found that the company cannot continue to allow its accounts receivable and inventory to increase at the same rate.CLARKSON LUMBER CASE STUDY – FINAN 6022-002 †¢ PAGE 3 The final issue we noticed was the accounts payable 2% discount. Clarkson was offered a discount if it pays off its payables to its suppliers within t en days. Even though there is value here, Mr. Clarkson said the company has taken few purchase discounts in recent years. Exhibit 3 attests to this as the company pays its suppliers on an average of 38 days. If the company used this discount on its financial projections, it would receive a purchase discount of $86K to add to its operating income.However, the trade-off is that Clarkson will have a significantly lower amount in accounts payable and will need financing to pay down these payables in order to obtain the discounts. If the company does not proceed with the discount, it will experience significantly lower net income, but will not need as much external financing. RECOMMENDATIONS One of our preferred recommendations for the company would be to replace some, or all, of the short term debt with a long term note. If the company used the amount of the external financing, about $975K, at 6% for 10 years, Clarkson will pay $130K a year.At 15 years, the company will be paying $99K a year. Or the company could use half of the external financing amount, roughly $488K, at those same terms and pay $65K or $49K for ten years or fifteen years, respectively. These numbers indicate that by replacing short-term debt with long-term debt, Clarkson will be making smaller payments at a lower interest rate, freeing up additional cash flow. Another way Clarkson can increase their cash flow is by decreasing the accounts receivable period.In Exhibit 3, we can see that on average the company takes 39 days to collect from accounts receivable and the company has a cash cycle of 55 days, meaning there is a 55 day delay between paying for inventory and collecting the sale. Thus, we recommend that the company use a stricter policy for collections for its customers. For example, if Clarkson could require payments in 30 days, their cash cycle drops to 45 days. By decreasing the accounts receivable period, the company can collect cash more quickly and will pay less in finance CLARKSON LUMBER CASE STUDY – FINAN 6022-002 †¢ PAGE 4 harges. The cash collected from accounts receivable can then be used to manage accounts payable. Our next recommendation is based on Clarkson’s need to increase the amount of cash available, thus capitalizing on growth opportunities. From 1993-1995, the company’s need for increased financing despite profitability comes from Mr. Clarkson’s buyout of Holtz’s share of the company, as well as the increase in inventory and accounts receivable as explained above. It is important for Clarkson Lumber to have access to larger amounts of cash to support its growth in the short and long term.Clarkson’s current success is due to the ability to compete on price; thus a large growth opportunity exists if they can continue to use trade discounts. If the company can use trade discounts, they will receive a purchase discount of around $86K added to income. The trade-off comes from the company having significa ntly lower accounts payable. In the long run the company will clearly need the additional credit, shown by the internal growth rate of 6. 1% and a projected sales growth of 21. 7%.The company will also need to alter the equity/debt ratio due to the projected growth rate of sales in 1996 which is greater than their sustainable growth rate of 15. 8%. Clarkson Lumber will potentially start producing positive free cash flows, as long as their growth rate stabilizes at a more reasonable rate. Our recommendations are aimed at producing positive free cash flows sooner, and the increase in quantity discounts will lower the cost of goods of sold and offset the financial obligations. If the $750,000 line of credit is extended by Northrup Bank, then debt and interest expenses will increase.This creates even more of a necessity to apply the increase in available credit in such a way that will reduce costs. CLARKSON LUMBER CASE STUDY – FINAN 6022-002 †¢ PAGE 5 EXHIBIT 1 CLARKSON LUMB ER COMPANY INCOME STATEMENT 1993 NET SALES COGS: BEGINNING INVENTORY PURCHASES ENDING INVENTORY TOTAL COGS GROSS PROFIT OPERATING EXPENSES EBIT INTEREST EXPENSE NET INCOME BEFORE TAXES PROVISION FOR TAXES NET INCOME 1994 1995 1ST QTR 1996 $2,921 $3,477 $4,519 $1,062 $330 $2,209 $2,539 $337 $2,202 $337 $2,729 $3,066 $432 $2,634 $432 $3,579 $4,011 $587 $3,424 $587 $819 $1,406 $607 $799 $719 $622 $97 $23 $74 $14 $60 $843 $717 126 $42 $84 $16 $68 $1,095 $940 $155 $56 $99 $22 $77 $263 $244 $19 $13 $6 $1 $5 CLARKSON LUMBER CASE STUDY – FINAN 6022-002 †¢ APPENDIX EXHIBIT 2 CLARKSON LUMBER COMPANY BALANCE SHEET 1993 1994 1995 1ST QTR 1996 CASH ACCOUNTS RECEIVABLE, NET INVENTORY CURRENT ASSETS FIXED ASSETS TOTAL ASSETS $43 $306 $337 $686 $233 $919 $52 $411 $432 $895 $262 $1,157 $56 $606 $587 $1,249 $388 $1,637 $53 $583 $607 $1,243 $384 $1,627 NOTES PAYABLE, BANK NOTE PAYABLE TO HOLTZ (CPLTD) NOTES PAYABLE, TRADE ACCOUNTS PAYABLE ACCRUED EXPENSES TERM LOAN, CURRENT PORTION CURRENT LIABILITIES TERM LOAN NOTE PAYABLE TO HOLTZ TOTAL LIABILITIESNET WORTH $0 $0 $0 $213 $42 $20 $275 $140 $0 $415 $504 $60 $100 $0 $340 $45 $20 $565 $120 $100 $785 $372 $390 $100 $127 $376 $75 $20 $1,088 $100 $0 $1,188 $449 $399 $100 $123 $364 $67 $20 $1,073 $100 $0 $1,173 $454 TOTAL LIABILITIES AND NET WORTH $919 $1,157 $1,637 $1,627 CLARKSON LUMBER CASE STUDY – FINAN 6022-002 †¢ APPENDIX EXHIBIT 3 1993 1994 1995 AVERAGE LOW PROFIT OUTLETS HIGH PROFIT OUTLETS COGS OPERATING EXPENSE CASH ACCOUNTS RECEIVABLE INVENTORY FIXED ASSETS TOTAL ASSETS PURCHASES 75. 39% 21. 29% 1. 47% 10. 48% 11. 54% 7. 98% 31. 46% 75. 62% 75. 75% 20. 62% 1. 50% 11. 82% 12. 42% 7. 54% 33. 28% 78. 49% 5. 77% 20. 80% 1. 24% 13. 41% 12. 99% 8. 59% 36. 22% 79. 20% 75. 64% 20. 91% 1. 40% 11. 90% 12. 32% 8. 03% 33. 65% 77. 77% 76. 9% 22. 0% 1. 3% 13. 7% 12. 0% 12. 1% 39. 1% 75. 1% 20. 6% 1. 1% 12. 4% 11. 6% 9. 2% 34. 3% PERCENT OF TOTAL ASSETS: CURRENT LIABILITIES LONG-TERM LIABILITIES EQUITY 9. 41% 4. 79 % 17. 25% 16. 25% 6. 33% 10. 70% 24. 08% 2. 21% 9. 94% 16. 58% 4. 44% 12. 63% 52. 7% 34. 8% 12. 5% 29. 2% 16. 0% .54. 8 CURRENT RATIO RETURN ON SALES RETURN ON ASSETS RETURN ON EQUITY 2. 49 3. 32% 6. 53% 11. 90% 1. 58 3. 62% 5. 88% 18. 28% 1. 15 3. 43% 4. 70% 17. 15% 1. 74 3. 46% 5. 70% 15. 78% 1. 31 -0. 70% 1. 80% -14. 30% 2. 52 4. 30% 12. 20% 22. 10% 6. 85 53. 28 9. 70 37. 63 9. 53 38. 32 90. 91 52. 60 6. 72 54. 31 8. 89 41. 07 9. 56 38. 16 95. 38 57. 22 6. 79 53. 80 9. 29 39. 35 9. 55 38. 24 93. 15 54. 91 6. 24% 18. 28% 19. 03% 25. 90% 4. 94% 17. 15% 29. 97% 41. 49% 6. 06% 15. 78% 24. 50% 33. 69% PERCENT OF SALES: INVENTORY TURNOVER (AVG) INVENTORY PERIOD RECEIVABLES TURNOVER RECEIVABLES PERIOD PAYABLES TURNOVER PAYABLES PERIOD OPERATING CYCLE CASH CYCLE INTERNAL GROWTH RATE SUSTAINABLE GROWTH RATE ACTUAL GROWTH MARGIN ASSET GROWTH MARGIN 6. 98% 11. 90% CLARKSON LUMBER CASE STUDY – FINAN 6022-002 †¢ APPENDIXEXHIBIT 4 CASH FLOWS FOR CLARKSON 1994 1995 1993 T0 1995 $68 ($105) ($95) $127 $3 $77 ($195) ($155) $163 $30 $145 ($300) ($250) $290 $33 CASH FROM OPERATIONS ($2) ($80) ($82) SOURCE OF CASH: CASH FROM OPERATIONS CASH FROM BANK LOANS SOURCES OF CASH: ($2) 60 $58 ($80) 330 $250 ($82) 390 $308 $29 $20 $49 $126 $20 $100 $246 $155 $40 $100 $295 $9 $4 $13 CASH FROM OPERATIONS NET INCOME CHANGE IN A/R CHANGE IN INVENTORY CHANGE IN N/P – TRADE CHANGE IN ACCRUED EXP. USE OF CASH FIXED ASSETS CPLTD HOLTZ LOAN USE OF CASH CHANGE IN CASH CLARKSON LUMBER CASE STUDY – FINAN 6022-002 †¢ APPENDIX EXHIBIT 5CLARKSON LUMBER COMPANY FORECASTS PROJECTED INCOME STATEMENT WITH PURCHASE DISCOUNT PROJECTED INCOME STATEMENT WITHOUR PURCHASE DISCOUNT 1996 NET SALES COGS: BEGINNING INVENTORY PURCHASES* 1996 $5,500 ENDING INVENTORY TOTAL COGS** $587 $4,279 $4,866 $708 $4,158 GROSS PROFIT OPERATING EXPENSES*** EBIT PURCHASE DISCOUNT**** INTEREST EXPENSE***** NET INCOME BEFORE TAXES PROVISION FOR TAXES NET INCOME NET SALES COGS: BEGINNING INVENTORY PURCH ASES $1,342 $1,150 $192 $86 $93 $185 $55 $130 ENDING INVENTORY TOTAL COGS 1996 ASSETS CASH A/R, NET INVENTORY CURRENT ASSETS FIXED ASSETS TOTAL ASSETS 1996 LIABILITIESA/P (10 Days of Purchases) ACCRUED EXP. (1. 5% of Sales) CPLTD BANK NOTE PAYABLE (PLUG) CURRENT LIABILITIES LT DEBT TOTAL LIABILITIES NET WORTH TOTAL LIABILITIES AND NET WORTH $1,342 $1,150 $192 $93 $99 $41 $58 PROJECTED BALANCE SHEET PROJECTED BALANCE SHEET $77 $655 708 $1,440 $411 $1,851 $587 $4,279 $4,866 $708 $4,158 GROSS PROFIT OPERATING EXPENSES EBIT INTEREST EXPENSE NET INCOME BEFORE TAXES PROVISION FOR TAXES NET INCOME * Purchases based on average percentage of Sales (77. 8%) ** Total COGS based on average percentage of Sales (75. 6%) *** Operating Costs based on average percentage of Sales (20. 1%) **** 2% Discount on Purchases of $4,277 ***** 11% on the LOC and 10% on Term Loan ASSETS CASH (1. 4% of Sales) A/R NET (11. 9% of Sales) INVENTORY CURRENT ASSETS FIXED ASSETS* TOTAL ASSETS $5,500 $117 $83 $20 $972 $ 1,192 80 $1,272 $579 $1,851 0. 075 77 655 708 1440 411 1851 LIABILITIES A/P ACCRUED EXP. CPLTD BANK NOTE PAYABLE (PLUG) CURRENT LIABILITIES LT DEBT TOTAL LIABILITIES NET WORTH $465 83 20 $696 $1,264 80 $1,344 $507 TOTAL LIABILITIES AND NET WORTH $1,851 * I used the average total assets of sales percentage and backed into Fixed Assets CLARKSON LUMBER CASE STUDY – FINAN 6022-002 †¢ APPENDIX