Slavery And The Slave Trade - 1889 Words

For over 2,000 years, slavery has been conducted in various parts of the world. From year 1500 to year 1900, Europeans stole individuals from West Africa, West Central Africa, and Southeast Africa and shipped them to the different parts of the Atlantic. This process dehumanized them of their identity. Europeans stole husbands, wives, merchants, blacksmiths, farmers, and even children. They removed them from their homelands and gave them new names: slaves. European slaveholders never thought to take ownership of their actions by killing humans with brutality and degradation. Slave trade was considered popular in England and soon after more countries began the process of taking slaves to newly claimed territories. These countries include†¦show more content†¦Of that 12.5 million Africans, 1,061,524 were from Spain, 5,848,266 were from Portugal, 3,529,441 were from Great Britain, 554,336 were from the Netherlands, 305,326 were from the United States, 1,381,404 were from France , and 111,040 were from Denmark. Britain began to slave trade largely through private trading companies in the 1640s. The London-based Royal African Company was extremely important to the use of slavery in 1672. The amount of voyages to Africa made between 1695 and 1807 from each of the main European docks that were involved in the slave trade was Liverpool, London, and Bristol. Liverpool contained 5,300, London contained 3,100, and Bristol contained 2,200. Other European ports were held in Amsterdam, Barcelona, Bordeaux, Cadiz, Lisbon, and Nantes containing 450. In the early 1700s, many merchants came from London and Bristol. On the other hand, Liverpool was increasing as well from the 1740s surpassing their opponents. Even though London and Bristol were taking trips back and forth to Africa, Liverpool dominated both of them and continued until abolition in 1807. Liverpool was the most involved ports in slaving during the 18th century. During 1500 to 1900, slavery in the southern part of America was assumed the worst in all of slavery. Slavery in the South was believed to be harsher and wicked than slavery in Latin America. The Catholic Church in South America vowed to give slaves a

Literature Review of Myob Application Package in Australia

Question: Discuss about theLiterature Review of Myob Application Package in Australia. Answer: Introduction: Mind Your Own Business or MYOB is a financial software package which provides accounting, tax and other services to medium and small businesses. It is a multinational corporation based in Australia and is a public company. There are two different versions of MYOB accounting software MYOB LiveAccounts, which is a cloud application, and MYOB Basics, the desktop-only software. Its products are used by 1,000,000 business users and 10,000 accounting practitioners. It is well known New Zealand and Australia. This literature review discusses the two versions of MYOB software stating its history with the help of Christopher Lee, adoption, and growth of the company mentioning the Lean Startup concept model and anchor cord for overseeing its production and quality. In-depth explanations include the current size of the financial market globally, other competitors in the market, which offers almost similar features and performance of MYOB software packages. Analyzed the different advantages MYOB provides over other competitors including less hassle of hardware, cost savings, real-time update of reports, and automation of entries. This review also mentions the current limitations MYOB is facing and the gaps the company wants to address. Literature Review History Christopher Lee and Team Teleware, Inc. used the name MYOB in their accounting software in the 1980s in the United States. Christopher Lee provided the equity to Data-Tech Software, the Australian publisher and in 1996 it purchased the intellectual property rights. The company changed the name to MYOB and was registered on Australian Stock Board Exchange or ASX on 9th July 1999 (Myobecommerce.com.au, 2016). MYOB extended its practices in Australia and New Zealand, after it merged with Solution 6 Holdings in 2004, after finding success in the business and expanded it products and services for the same. In May 2008 MYOB released online services such as email hosting, web hosting, and domain registration. Tim Reed replaced former CEO Craig Wrinkler as the new CEO in June 2008. In the same year, the company pulled off operations from Ireland, UK, USA, and Asia to focus only on Australia and New Zealand. After the equity consortium led by Archer Capital and purchased MYOB was sold to on 2 1 August 2011 for an unknown amount, and the company retained its private ownership (Myob.com, 2016). Development and Adoption To minimize waste and to follow the concept of stocking inventory as followed by Toyota, MYOB adopted the lean startup concept model for its software development cycle. Lean Startup concept focuses on creating products which are in demand and prevent unnecessary stocking of inventory by taking feedback inputs from the users system (Rathje Andersen, 2016). Another concept called Andon Cord had been adopted by the company to improve the production quality. Andon Cord is a literal cord which the employees can pull anytime if they notice any anomaly in the production, which can pose a threat to the safety or quality (Zealand345.rssing.com, 2016). The entire team then focuses solely on the problem until it is resolved and that nothing unnecessary goes out in public. For three years MYOB invested in a cloud platform, and in 2012 the company released the cloud version of its financial software called AccountRight Live (Myob.com, 2016). The cloud application failed to meet expectations, and the primary complaint of the users was its speed since they were migrating from the desktop-only version which offered good speeds. The company had many features lined up in its roadmap, but it took the feedbacks seriously and changed its roadmap to focus only on speed and performance. The company also decided to focus on power users, those who can work efficiently by memorizing keyboard shortcuts in reduced number of steps (Curtis, 2015). In 2014 the company started to welcome feedback and complaints from its users in the form of blogs or forums from all types of clients (Fletcher-Brown, 2015). Current Market Size The market for global financial services is expected to grow from $ 103.66 billion from $ 66.92 million in 2014 at a CAGR of 9.1%. The financial market is divided globally into the following regions North America, Europe, Asia-Pacific, Middle East and Africa, and Latin America. According to the regions the software categorized are Audit, Risk and Compliance Management, Analytics and BI applications, Business Transaction Processing, and Enterprise IT and Customer Experience (Zhang et al., 2016). Present Leaders in the Market There is several others competitive financial software in Australia offering similar performance and features. Financial cloud applications include Xero, Saasu and Intuit QuickBooks Online Simple Start. Desktop only financial applications are Reckon Accounts EasyStart and MoneyWorks Express (Symons, 2014). Competitive Advantage Migrating to Cloud gave users a lot of freedom in accessing the files from any place such as from clients home, onsite or own home. It helps in collaboration with customers, suppliers, and partners. It reduces the stress on the employees and strengthens the overall organization, which increases productivity and efficiency of the organization (Mohabbattalab, von der Heidt, and Mohabbattalab, 2014. Manual entries take up a lot of time, and human error can creep in if the workload becomes too high-inducing stress. MYOB automates them by removing duplicate entries and issues with redundancy. This software package sync information was thereby reducing the time consumed in making credit notes, purchase orders and more. Updates are reflected in real time, so the clients view the report instantly. It helps the organization in achieving financial stability by preventing the need for implementing multiple teams working on generating reports like payroll and account updates (Hol and Ginige, 2012) . According to Hossack (2015), operating systems, hardware, its maintenance and accounting fees take up a significant share of the company's revenue. Adopting to cloud application saves up a lot of costs and requiring a monthly subscription-based fee instead. The cloud application also takes care of the backups, updates, and maintenance on its requiring no human intervention. Present Challenges and Literature Gap of MYOB The underlining issue of data security persists when it comes to using cloud applications and according to Software Advice's survey, 46% of respondents who took part expressed this problem. Any data stored on the cloud is susceptible to hacking, theft, and frauds. MYOB is not novice-friendly, and the software company, therefore, trains their employees separately to use this program in workshops and seminars (Slocombe, 2013). Merging with Solution 6 may benefit the company achieve its recognition globally, and the merger can be beneficial in creating the company's branding, strong market presence. Other advantages include the ability to resolve issues between business users and accountancy, and closing the gap between them. However, Craig Winkler, the CEO of Solution 6 believes the merger will not bring the company any global recognition (ARN, 2016). Conclusion The company made a significant step by adopting Lean Startup Concept to minimize inventory stocking and Andon Cord, to prioritize problems related to production issues at hand by involving all the available employees. MYOB listened to its user feedback seriously and migrated to a cloud for its financial software package and on repeated complaints, the company focused on speed and performance instead of adding new features. MYOBs competitors include Reckon Accounts EasyStart Competitive cloud, MoneyWorks Express in desktop software, and for cloud applications, there are Xero, Saasu and Intuit QuickBooks Online Simple Start. MYOB is ahead of its competition by automating daily tasks, sync information, removes duplicate entries, and makes investment quite cheap. MYOB is not novice-friendly, for which the company organizes sessions as workshops and seminars to train employees. The concern with online data security remains. MYOB merged with Solution 6 to create brand value and recognition . However the CEO of Solution 6 thinks otherwise. Recommendations The biggest hurdle to MYOB is its user-friendliness and the fact that it has to organize seminars and workshops to train employees and clients separately can be its weak point. It has to redesign the interface with online tutorials and documentation so that anyone can learn it on his own with self-pace. It has to do research and make case studies on its competitors in implementing new features and services, and not solely rely on user feedbacks which can be limiting. It can look for expanding its business besides New Zealand and Australia for its revenue generation and also needs to include diversity to its workplace, and understand foreign market culture for setting up its business. References ARN. (2016).MYOB and Solution 6 to merge. [online] Available at: https://www.arnnet.com.au/article/116270/myob_solution_6_merge/ [Accessed 24 Aug. 2016]. Curtis, V., 2015.MYOB Software for Dummies-Australia. John Wiley Sons. Fletcher-Brown, R., 2015. Mind Your Own Businesshow can we best support employers to improve the mental health of their employees?.Perspectives in public health,135(1), pp.18-20. Hol, A. and Ginige, A., 2012. eT Guide-Assisting The eTransformation Journey: A Case Study Approach.International Journal on Advances in ICT for Emerging Regions (ICTer),4(3). Hossack, S., 2015. Cloud-based accounting and productivity tools for practitioners and taxpayers.Taxation in Australia,50(5), p.265. Mohabbattalab, E., von der Heidt, T. and Mohabbattalab, B., 2014. The perceived advantages of cloud computing for SMEs.GSTF Journal on Computing (JoC),4(1), p.61. Myob.com. (2016).The MYOB Story. [online] Available at: https://www.myob.com/nz/about/group/story [Accessed 24 Aug. 2016]. Myobecommerce.com.au. (2016).History General Information. [online] Available at: https://www.myobecommerce.com.au/history [Accessed 24 Aug. 2016]. Rathje Andersen, M., 2016. New approaches to early stage entrepreneurship. Slocombe, G., 2013. Cyber security--A vital part of national security.Asia-Pacific Defence Reporter (2002),39(2), p.31. Symons, M.J., Single Funnel Pty Ltd, 2014.Customer relationship management (crm) systems. U.S. Patent Application 14/192,692. Zealand345.rssing.com. (2016).The Pulse NZ From MYOB. [online] Available at: https://zealand345.rssing.com/chan-11352612/all_p2.html [Accessed 24 Aug. 2016]. Zhang, Z., Nan, G., Li, M. and Tan, Y., 2016. To Lead or to Follow? Market Entry and Pricing Strategies for Saas Provider.Market Entry and Pricing Strategies for Saas Provider (June 7, 2016).

Angelina Jolie essays

Angelina Jolie essays Imagine life through the eyes of Angelina Jolie. Abandoned at the age of one by her father, her mother was forced to give up her dream of acting to become a full time mom for Angelina and her brother, James Haven. Although Angelina and her father, Jon Voight, still kept in touch, their relationship was very distant and unloving. She claimed not to be able to respect a man who could leave his perfect family life for a career in acting. Being that both her mother, Marcheline Bertrand, and her father were in love with film making, and the theatre, she was forced into this business. Angelina began her career as an actress at the age of five, although her first official screen appearance wasnt until she was seven years old. Can you even imagine starting your future at the early age of five years? After this role she went on to perform in Hackers (where she met her ex-husband Johnny Lee Miller), FoxFire, and Cyborge 2. However she caught the publics eye with George Wallce (in which she won a Golden Globe for Best Supporting Actress). Follwing this she was awarded another Golden Globe, this time for Best Actress in the made for television film Gia. Next she began working on the film Pushing Tin. Angelina told People magazine I had so much fun working on this movie, everyone was high sprited and ready to produce a best seller. (Jolie, peoplemagazine. com, Angelina Jolie) Next came the most popular movies in the career of Jolie, Playing by Heart, Bone Collector, Girl, Interrupted (at which she was awarded best supporting actress), Gone in 60 seconds, and finally The Yes, Jolie, has a very lengthy list of star roles but her first real dream for the future was to become a funeral director. She told US Weekly: There's som ...

buy custom Hamlet essay

buy custom Hamlet essay Hamlet, Prince of Denmark is a play written by Shakespeare and majorly characterized by tragedies. It is all about a son who seeks revenge for the death of his father who was a king. In most plays, it is always fulfilling when the main character is a strong and noble person. A person who is tactfully and skillfully goes about his mission. He employs good measures to achieve his mission without failure. These culminate into a great success to the main character who becomes a hero for the achievements. This play however, is about Hamlet who is the son of a murdered Danish King Hamlet. This death had seriously affected his emotional balance. His ghost appears to Horatio, Hamlets best friend. He informs Hamlet of this but he refuses to accept until he sees it himself. The ghost of his father later appears to him and claims that he was murdered by his brother, the new King Claudius. He is Hamlet's uncle. He later married Hamlet's mother, Gertrude. The ghost tells him to revenge his death. Hamlet has a mission to accomplish. He sets himself to actually achieve this but does not know how to do this. King Claudius also appears guilty of the murder and feels threatened by Hamlets presence. He plans to get rid of him. Hamlet's mission has to be well organized before for its success. He therefore embarks on a mission to establish Claudius guilt. He therefore prepares a play in which they act about the slain father. He makes King Claudius watch to establish his reaction. Hamlet represents his father in the play. Then he becomes furious and storms out of the room as they play proceeds. This establishes Hamlet's suspicion that he indeed killed his father in order to take over the thrown. He even goes further to marry his mother. He remains with no doubt in his mind that his uncle is the suspect He delays in effecting his mission due religion. The environment seems Christian and this makes him think that revenge is not good for his faith. He thinks that it is the work of God. He even got the right opportunity to kill him in scene 3 but thinks that Claudius would go to heaven if killed while praying. He draws his sword and returns it back after much thought. He postpones his mission again to a much later date. Polonius is Hamlet's chief trusted counselor. He has a son called Laertes who returns to France and a daughter called Ophelia. She is courted by Hamlet This relationship runs into problems after Ophelia's father and brother warn her that Hamlet is not serious about their relationship. Soon after Ophelia realizes that his behavior has drastically changed. Her father gets concerned of this and reports to the King, who orders an investigation. Hamlet's constant mourning of the late father becomes the concern of the mother. He confronts the mother and a quarrel elapses between them. Apparently, Polonius hides within the vicinity to spy. He becomes convinced that Hamlet is indeed mad and worries that he may harm Gertrude. This prompts him to scream for help. Hamlet identifies Gertrudes father where he hides and stabs him to death. He is however not remorseful that he has killed his lover's father. He calls him, 'Thou wretched, rash, intruding fool'. Gertrude also gets convinced of Hamlets madness after the ghost to him telling him to be gentle to his mother but to kill King Claudius. The King sends Hamlet to England for a diplomatic mission. He does this due to fears for his life. He realizes that Hamlet may harm him. He sends Rosencrantz and Guildenstern to accompany the princes to England after disclosing to them that he is doing this to send the princes to his death trap. Hamlet's revenge is being delayed again as he cannot gain access to Claudius. While away, his quest to avenge his father's death intensifies. He meets a bloody fight that results in many deaths on his way. Another revenge tragedy happens when Ophelia gets mad due to her fathers death. She begins to walk around singing to herself. Her brother Laertes comes back from France and gets shocked by the father's death and the sister's madness. He is convinced by King Claudius that Hamlet is responsible for all the tragedies in his family. He tells him that the prince is alive in England. This besets him on a revenge mission against Hamlet. King Claudius unsuccessfully tries different strategy to kill Hamlet in his ship and to make it appear like an accident on his way back from England . He escapes unhurt but Rosencrantz and Guildenstern die in the process. The King then resolves to capitalize on Laertes hatred by organizes a fight between him and Hamlet with the knowledge that Laertes is good with swords. Laertes further promises to poison the head of his sword to kill the prince at the slightest scratch. The king on part goes ahhead to plan to poison him with wine if the first attempt fails. Ophelia commits suicide and her death is reported. At the funeral, Laertes blames Hamlet and curses him. Hamlet appears at this time and confesses his love for Ophelia. A fight breaks between them but they are separated by Claudius and Gertrude. Hamlet is then informed by Claudius of the fight with Laertes to mend fences. He readily accepts this fight against his friend Horatio's warning. The fighting day comes and all are set. They have several rounds without success in any of the sides. Gertrude then unknowingly toasts Hamlet using the poisoned wine. She drinks it. Attempts by the King to block her not to drink are too late. At this time, Laertes finds an opportunity and stabs Hamlet with his poisoned sword. The fight continues and Hamlet manages to use Laertes sword against him. Gertrude then announces her poisoning as she dies. Laertes reveals King Claudius plot to kill Hamlet as he dies. This prompts Hamlet to stab the king using Laertes sword. He goes further to force him to drinking his own poisoned wine to kill him. Hamlet then announces Prince Fortinbras of Norway as the probable king as he takes his last breath. Horatio remains to recount the whole story to Prince Fortinbras who comes in only to be met by a deadly scene of bodies. The theme of revenge in this play has been met by a number of tragedies. Many deaths have come about the same thing. The delay of Hamlet's revenge is the main cause of many deaths seen at the end of the play. One thing leads to the other as more and more people are sucked into the saga. It seems that could Hamlet have gone ahead with his mission earlier enough, then many deaths at the end could have been avoided. The delay has also worked well for the continuation of the play. It brought the flow of the play. This is Shakespeare's longest play ever. The delay of Hamlet's revenge has thus aided in the flow of the play. Hamlets emotional life has also been built by this delay. At first he is not sure of going ahead with the or not. This changes as time goes. The experiences he undergoes harden him to and make him believe of the reason to revenge. At the end everybody with revenge mission dies. This tells us of the inability of revenge to solve problems but to lead to more corruption. People should instead work on themselves. Buy custom Hamlet essay

Economics of Developing Countries Essay Example | Topics and Well Written Essays - 1000 words

Economics of Developing Countries - Essay Example This strategy aims to increase the domestic production and reduce the dependency on foreign imports. Outward looking strategy Outward looking strategies are not just related to primary exports, but lay more importance on the trade of employment opportunities and other strategies which increases the level of income in the country. Trade expansion is to be used for economic growth and the generation of employment opportunities. b) India’s trade policies have changed rapidly since independence. Before independence India made imports for even those products which could be manufactured in India. But after independence there was a change in strategy and more emphasis is being laid on exports rather than imports. Today India has a strong trade policy and lays more emphasis on exports and follows the import substitute industrialization policy and restricts its imports. India now uses trade expansion as an instrument for economic growth and the generation of employment opportunities. I t has been effective in improving India’s economy especially developing the agricultural economy. The overall trade policy is good for Tamil Nadu as Tamil Nadu has increased its agricultural income. c) Both India and china have been successful in increasing their exports and reducing their dependence on imports. China has laid emphasis on the export of manufactured products, while India has laid much emphasis on the export of services. India’s exports are of capital and skill intensive products, while china’s exports are labor intensive goods. Both the countries have reduced their imports by the Import substitute industrialization strategy. Question 6: The article ‘Now we are seven billion’ states that Population growth has both positive and negative effects. Mr. Simon is of the opinion that prices would rise in real terms, when there is an increase in population. The article states that as the world economy boomed the population growth fell. Accord ing to the UN’s population division the world population will reach 7 billion as on 31st October 2011. According to Mr. Simon, the world’s rising population was not a problem since an increase in population is also related to an increased demand for investment. The author provides the example of China, where fertility is less and one child is the policy in the nation. The author states that china’s policy is a violation of rights. Encouraging smaller families is good for economic growth as it reduces the poverty in the country, but there are large families too. Although there is a basic view that rising population creates scarcity of resources, yet population is important for the economic growth of the country. The argument presented is that smaller families create economic growth. Smaller families create economic growth because smaller families’ means less poverty and each member of the family gets all the comforts of the life. Therefore this results in better economic growth of the country. The argument presented against is that when the population decreases then it reduces the growth of the economy, which again hampers the economic growth of the country. Thus population has both positive and negative effects. Question: V: DEEP in the South Atlantic, a huge business operation is under system that Brazil’s leaders say will turn their state into an oil power by the end of this decade. If the ambitious plans of the national oil

Antigone Essay Example | Topics and Well Written Essays - 750 words

Antigone - Essay Example p.). Of course, there are many other issues present in this tragedy; however, this paper would try to focus on the issue of laws, specifically on what would have happened when there would be no balance between the law of the gods and the law of man. In this case, this paper would try to cite different passages in the tragedy that may help illustrate on how the law of the gods were treated with respect of the law man, and on what may be its effects on Greek society as represented in the text. Body One of the main preludes to the tragedy was the civil war that happened in Thebes. The main participants in the civil war, on which the victor would be able to control the throne, were the brothers Polyneices and Eteocles (â€Å"Antigone† n. p.). However, both Polyneices and Eteocles where actually killed in the civil war, making way for Creon to actually occupy the throne (â€Å"Antigone† n. p.). In this case, Creon actually decreed that Eteocles would be honored while Polynei ces would be publicly humiliated through depriving him of burial, leaving his body to worms and vultures (â€Å"Antigone† n. p.). ... gh burying her alive in the cave (which was contrary to the law of the gods), starting the debate of Antigone and Creon on which law must actually be followed, the law of man (which is Creon’s law) or the law of the gods (â€Å"Antigone† n. p.). According to Antigone, the law of Creon must not be followed and that she has the moral obligation to bury the body of her brother despite it being contrary to the law given by him, given that such kind of law actually runs in contrary to the laws of the gods, making the decree of Creon morally corrupt and against the will of the gods (â€Å"Antigone† n. p.). According to Antigone, Yes; for it was not Zeus that had published me that edict; not such are the laws set among men by the justice who neither dwells with the gods below; nor deemed I that thy decrees were of such force, that a mortal could override the unwritten and unfailing statutes of heaven†¦Not through dread of any human pride could I answer to the gods for breaking these. Die I must—I knew that well (how should I not?)—even without thy edicts. But if I am to die before my time, I count that a gain: for when any one lives†¦can such any one find aught but gain in death? So for me to meet this doom is trifling grief; but if I had suffered my mother's son to lie in death an unburied corpse, that would have grieved me; for this, I am not grieved. And if my present deeds are foolish in thy sight, it may be that a foolish judge arraigns my folly. (â€Å"Antigone† n. p.) Despite such arguments by Antigone, however, Creon still stood ground in the law that he made, and even strengthened obedience to the law by creating a harsher punishment for Antigone (â€Å"Antigone† n. p.). In this case, Creon actually reasoned that there is no man that must be above law, or must

Retigabine for Seizures

Retigabine for Seizures Definition Ezogabine (United States) or retigabine (Europe) has the chemical name N-[2-amino-4-(4-fluorobenzylamino) phenyl] carbamic acid ethyl ester. It was shown that the anticonvulsive action of ezogabine is a consequence of its ability to open the KCNQ (Kv7)-type potassium channels that are composed of four subunits and are found in the membranes of neurons [2]. The importance of this type of potassium channels in the development of epilepsy was understood only after its dysfunction was linked to benign familial neonatal convulsions [3,4]. Ezogabine binds to all subtypes of the KCNQ potassium channels, including the KCNQ2-5- subtypes that are expressed in brain tissue. The especially heteromeric KCNQ2/3and KCNQ3/5 potassium channels are highly expressed in the central nervous system and more important in the control of neuronal excitability than other types because they mediate M currents [5,6]. Ezogabine is the only anticonvulsant that has a mechanism of action that involves opening potassium channels. This fact was the initial rationale for the drug’s development, as researchers sought to produce a new drug that would be effective in patients with drug therapy-resistant epilepsy. Ezogabine is the first antiepileptic drug with this mechanism of action and was developed to fill this gap and help with the treatment of drug-resistant patients. Finally, clinical trials documented the effectiveness of ezogabine as adjuvant therapy for the reduction of partial-onset seizure frequency, and it received marketing authorization in 2011 in both the United States and Europe [17] The properties Ezogabine is a poorly water soluble small molecule (molecular weight 303.3). ]. The standard method for identification of ezogabine is reverse phase high performance liquid chromatography (RP-HPLC) with or without mass spectrometry using electro spray ionization and quadrupole time-of-flight mass analyzer [19]. The results of ezogabine identification could be confirmed by nuclear magnetic resonance spectroscopy and infrared spectroscopy [19]. Mechanism of action The mechanism of action of ezogabine was investigated using the electrophysiological measurements of ionic currents in Chinese hamster ovary (CHO) cells (transfected with cDNA encoding humanM1 muscarinic receptors,KCNQand CD8cDNAs) and rat ganglion cells, using the amphotericin-B perforatedpatch technique [22]. The effects of ezogabine were tested on ionic currents from both heteromeric KCNQ2/3 and homomeric KCNQ1, KCNQ2, KCNQ3 and KCNQ4 potassium channels. The potassium currents were enhanced by ezogabine through all types of channels, except KCNQ1. The effects of ezogabine were also tested in another study on HEK293 cells stably transfected with KCNQ5 channels [23]; it was shown that ezogabine concentration-dependently also enhances the potassium current through this type of channel. After binding for the KCNQ channel, ezogabine decreases the membrane  potential threshold for activation of the channel (makes it more negative, i.e., shifts it toward the hyperpolarizing end) and in creases the probability of maximum opening of the KCNQ channel [22,23]. All of these effects make neurons less prone to depolarization and activation. Pharmacokinetics and metabolism The absolute bioavailability of orally-administered RTG is ~ 60% [34]. Absorption is rapid and Cmax is typically reached 30 120 min after a single oral dose [35-38]. Cmax is moderately increased when RTG is taken with a high-fat meal, while the area under the plasma concentration-time curve (AUC) remains unchanged [39]. RTG is rapidly eliminated following first-order kinetics, with a terminal half-life of approximately 7.5 h; the clearance is 0.58 0.76 l ·h-1 ·kg-1 [35-37]. Young women may reach 30% higher Cmax values than men after accounting for body weight, but weight adjusted clearance is similar [36]. RTG has a large volume of distribution (8.7 l ·kg-1) and a plasma protein binding of about 80% [35,39]. In healthy volunteers, RTG pharmacokinetics is linearly dose-proportional for doses of 50 350 ÃŽ ¼g BID and not affected by multiple administrations indicating that RTG does not influence its own metabolism [35]. In epilepsy patients, RTG dose linearity was demonstrated over the therapeutic dose range of 200 400 mg t.i.d. [35,40]. RTG is not metabolized by cytochrome P450 (CYP) enzymes [41,42]. Rather, it is extensively metabolized by N-glucuronidation, leading to formation of two major N-glucuronides, and to a smaller extent by N-acetylation, leading to formation of the N-acetyl metabolite of retigabine (NAMR, formerly AWD21-360), which also undergoes glucuronidation [41,42]. In vitro assays using recombinant human UDPglucuronosyltransferases (UGTs) identified UGT1A1, 1A9, 1A4, and 1A3 as the principal enzymes catalyzing RTG glucuronidation [43,44]. In subjects with reduced UGT1A1 metabolic capacity (Gilbert’s syndrome), RTG pharmacokinetics is unchanged and N-acetylation partially compensates for reduced glucuronidation, in addition to compensation by other UGT1A isoforms [45]. Other UGT1 and UGT2 family members also appear to be involved, because complete loss of UGT1A metabolic capacity (Crigler-Najjar type II) did not completely abolis h RTG glucuronidation in vitro [44]. Individuals with genetic polymorphisms in the N-acetyltransferase 2 (NAT2) gene leading to a â€Å"slow acetylation† phenotype had a lower total exposure to NAMR than rapid acetylators [45]. Safety and tolerability of RTG treatment is apparently not altered in subjects with Gilbert’s syndrome or slow acetylation polymorphisms [45]. RTG and its metabolites are primarily excreted by the kidney [42,45]. A 30% slower RTG clearance in elderly subjects vs. young subjects is consistent with the known decline of renal function with age [36]. Systemic RTG clearance can be reduced by 50% in patients with moderate/severe impairment of liver function (Child-Pugh score †¡ 7) or kidney function (creatinine clearance Safety and tolerability Three Phase III clinical trials were pivotal to the eventual approval of ezogabine for use to treat seizures. The first was a study by Porter et al. during which placebo or ezogabine  at daily doses of 600, 900, or 1200 mg was administered [9]. RESTORE 1 compared placebo to ezogabine 1200 mg/day, and RESTORE 2 compared subjects taking 600 or 900 mg  of ezogabine daily with those taking placebo [4,10]. As would be expected and consistent with other antiepileptic agents, the most commonly observed adverse effects seen with ezogabine use are CNS-related. At least 10% of study participants in Phase III clinical trials experienced somnolence, fatigue, confusion, dizziness, tremor, abnormal thinking, vertigo,  speech disorders, or amnesia [4,9,10]. Most of these adverse effects appear to be related to dose, and are typically reported to be mild or moderate in nature. As in the Phase III trials, the majority (62%) of adverse events were CNS-related. In addition, several ezogabine user s experienced neuropsychiatric events including hallucinations (2%), confusion (9%), and psychosis (1%) [12]. The majority of these episodes occurred within the first two months of drug exposure in individuals with no documented history of a psychiatric disorder.