Cyclo-oxygenase inhibitors of human diseases Essays

Cyclo-oxygenase inhibitors of human diseases Essays Cyclo-oxygenase inhibitors of human diseases Essay Cyclo-oxygenase inhibitors of human diseases Essay Historical background Cyclooxygenase ( COX ) inhibitors are a widely prescribed group of febrifuges and anodynes worldwide and are of import constituent in the intervention of inflammatory conditions. Although first COX inhibitor was discovered more than a decennary ago their beginning day of the months back to ancient Mediterranean descent1. Back and other organic structure strivings where treated utilizing infusions of poplar tree bark and foliages of Vinca minor. Use of willow bark emerged far more recently and its first visual aspect was reported in England in 17631. As was subsequently discovered, the kernel of the willow bark possessing anti-inflammatory and antipyretic belongingss was salicin. Further alteration of its structural belongingss allowed coevals of salicylic acid that finally was developed via Kolbe reaction utilizing phenol1,3. In 1899 Bayer company went in front in synthesizing more susceptible derived function of it, acetylsalicylic acid and named it aspirin. Following this Butazolid in ( 1949 ) and Indocin ( 1963 ) came along nevertheless the enigma of mechanism of their action in the organic structure was non yet developed. It was non known until 8 old ages subsequently when an thought environing the synthesis of prostaglandins within organic structure was revealed and for which a Nobel Prize in physiology and medical specialty was awarded ( 1982 ) 1. It was proposed that first non-steroidal anti-inflammatory drug ( NSAID ) , aspirin, acted upon suppression of an enzyme that played function in using unsaturated fatty acids into biochemical molecules exercising their action in conditions such as redness, hurting, and febrility and thrombocyte synthesis. It was accepted that during alterations happening within stimulated cells and tissues prostaglandins synthesis was taking topographic point 1,3. Structure of COX was isolated in 1976 and its 2nd isoform was confirmed around 14 old ages subsequently by few different research lab probes ; probes which greatly allo wed appreciating the nature of first nonselective cyclooxygenase inhibitors NSAIDs in the intervention of human diseases1. 1.1 The pharmacological medicine and chemical science of Cox enzyme Cyclooxygenase ( COX aka PGG2/H2 synthase ) belongs to the household of enzymes known as myeloperoxidases and it is the important enzyme in the synthesis of prostaglandins, prostacyclin and tromboxane A2 resullting from the transition of arachidonic acid ( AA ) 2,4. This heme-containing COX enzyme is a bifunctional biocatalyst with two interrelated active sites: Cox and peroxidase which action involves coevals of hydroperoxy endoperoxide PGG2 via Cox rhythm ( Fig.1. ) into its decreased signifier of hydroxy endoperoxide ( PGH2 ) ( Fig. 2. ) 2,4. Both isoforms of COX enzyme are expressed in endothelial, monocytic and nephritic cells with COX-2 being more profound in inflammatory and malignant neoplastic disease tissues. Both enzymes are characterised by signal peptide, endothelium growing like factor ( EGF ) part, membrane in-bound sphere, catalytic portion, interface between monomers and N-linked polyoses residues2. The signal peptide in COX-1 consists of 23 residues whereas COX-2 has merely 17. The EGF like part constitutes a major portion of the interface and is non found in other myeloperoxidases. It is involved in Cys-Cys cross linked Bridgess with deficiency of Cys9 in COX-1 and Cys512 in COX-2. The membrane in-bound sphere histories for 33 % of overall similarity and 24 % of individuality within membranous face. This sphere is described as consisting of 4 amphipathic a spirals that surround the entry to the COX site. The catalytic portion is known to be the largest portion of the enzyme with remained homology between other myeloperoxidases. 180 A ; deg ; rotary motion between fractional monetary units is preserved with chemical interaction between polar, ionic and hydrophobic medieties. Differences in residue positioning prevent heterodimerization and dissociation from facial interaction inactivates the enzyme s overall catalytic activity 1,2,3,4,5. Figure 1. Mechanism of COX rhythm in Cox active site demoing free groups formation denoted by? anterior to PGH2 synthesis in POX tract ( non shown ) 2. Attraction of H atom from Tyr385 by peroxyl group of PGG2 allows for the regeneration of the stairss of the reaction in the COX rhythm of prostanoid biogenesis. The colored boxes are to bespeak the beginning of O atoms. PLA2 phospholipase A2, S secretory, C cytoplasmic. Figure 2. A diagram summarising alterations made to AA in the distinguishable active sites of the PGG2/H2 synthase and merchandises formed via action of each catalytic active site 2. 1.2 The nature of Cox suppression in the human organic structure Inhibition of Cox action is desired in the intervention of human diseases. Not merely because it suppresses the inflammatory production of prostaglandins in the conditions such as: dysmenorrhoea, arthritic arthritis, degenerative arthritis but besides because it prevents platelet collection, suppresses tumour growing and prevents cancer5. Until 1994 it was non clear by which manner, mechanism or procedure suppression of COX was carried out. Just complexation surveies between COX and Ansaid allowed insight into molecular footing of COX suppression. The probe led by Garavito and his co-workers proposed such theoretical account of suppression. In his theoretical account it was suggested that the enzyme in inquiry possesses long hydrophobic way that originates from in-membrane edge mediety up to the bosom of the dimer fractional monetary unit. Barricading this channel stops the endogenous substrate ( AA ) from adhering hence possible intercession in the procedure of prostaglandins biosyn thesis5. 1.3 The types of Cox inhibitors in the intervention of human diseases There are several types of COX inhibitors available in the intervention of human diseases. The really first one, acetylsalicylic acid, is known to move through non-selective and irreversible mode. As this mode suggests aspirin binds to both types of COX enzyme by acetylizing Ser530 residue upon covalent alteration. Consequently effects such as hazard of inordinate hemorrhage, ulcer formation or fetal distortion bound the usage of acetylsalicylic acid in covering with long term diseases. Nowadays it is chiefly considered as the of import constituent in the intervention of cardiovascular conditions due to its anti-platelet activity 1,3. Other types of non-selective NSAIDs such as Feldene, isobutylphenyl propionic acid or diclofenac, constitute bulk of curative agents being prescribed nevertheless due to harmful effects they are being considered less effectual in the long term intervention. The harm to the gastrointestinal ( GI ) system is due to suppression of COX-1 expressed in GI mucous membrane which consequences in formation of ulcers with associated hemorrhage. Therefore since the chief mark for taking those drugs is found to be of inflammatory nature ( suppression of COX-2 ) they are nowadays preferred in topical dose signifiers 1,3,5. The effect of the unsought effects caused by non-selective COX inhibitors targeted new attack towards development of more specifically moving agents. The epoch began on find of the 2nd isoform of Cox and debut of first COX-2 selective agent ( 1999 ) was introduced to the market within 10 old ages since its find with Celebrex and Vioxx for the intervention of arthritis. The find proposed mechanism of actions of both enzymes within the organic structure with COX-1 possessing more constituent effects particularly in GI piece of land. It was hence suggested that COX-2 was an inducible signifier in conditions such as redness and hurting, symptoms desired in intervention of human diseases associated with the effects of COX-2 isozyme 1,3. 2. ASPIRIN THE ORIGINAL COX INHIBITOR ( Joyce ) 2.1. Pharmacology and chemical science of Aspirin Plant ingredient salicin was discovered in the willow bark and leaves in the seventeenth century by a Greek doctor ( Hippocrates ) who prescribed it as an analgetic and antipyretic. Further into the seventeenth century a rough signifier of salicylic acid was made by a German scientist ( Charles Frederic von Gerhardt ) . This was followed by production of a purer signifier of salicylic acid by another German chemist ( Karl Johann Kraut ) . Finally in 1897 a German chemist Felix Hoffmann, who worked for the pharmaceutical company Bayer, was assigned the undertaking to happen a better derived function of salicylic acid. He besides had his ain personal grounds for desiring to happen a better derived function. His male parent had been taking salicylic acid for his arthritis hurting but could no longer take it without vomiting3,7. In 1889 Hoff adult male so found a manner of acetylizing the hydroxyl group on the benzine ring of salicylic acid to organize acetylsalicylic acid. Hoffman father tried the new derivative and it was pronounced effectual. The name A ; lsquo ; ASPIRIN was given to the drug by Bayer main pharmaceutical chemist Henrich Dreser7. Aspirin was found to hold antipyretic, analgetic and anti-inflammatory effects. It does this by suppressing cyclo-oxygenase ( COX ) or prostaglandin endoperoxide synthase ( PGHS ) enzyme irreversibly. COX is responsible for cyclizing arachidonic acid and adds the 15-hydroperoxy group to organize PGG2 which is the precursor to prostaglandins. An enzyme perioxidase is responsible for cut downing the hydroperoxy group of PGG2 to the hydroxyl group of PGH2. ( 4 ) ( See Figure 15- prostaglandins synthesis ) Prostaglandins can be described as chemical go-betweens that produce a assortment of strong physiological effects in the organic structure. Most significantly they are responsible for the activation of the inflammatory response, production of hurting, and febrility. There are three isoforms of the COX enzyme of which acetylsalicylic acid has an consequence on two which are COX-1 and COX-2. Aspirin binds covalently modifiying COX-1 through acetylation of its Ser-530 and COX-2 through acetylation of its serine 516 residue by puting a bulky component ( ethanoyl group ) and this straight inhibits binding of arachidonic acid. Aspirin s action is more powerful against COX-1 than against COX-2. This difference in suppression of the two COX enzymes by acetylsalicylic acid is due to the larger volume of the COX-2 active site produced by the Val-523 permutation at the side pocket. ( 1,7, 9 ) The difference in the size of the active site has been exploited by pharmaceutical companies to develop selective COX-2 inhibitors ( subdivision 4 ) COX-1 is an indispensable enzyme expressed in bulk of tissues and besides in thrombocytes. It is responsible for prostaglandin production involved in homeostatic mechanisms e.g. thrombocyte collection, stomachic wall protection, ordinance of nephritic blood flow and induction of labor in childbearing. In contrast, COX-2, is an inducible signifier which becomes up regulated by inflammatory go-betweens such as cytokine ( Interleukin and tumour mortification factor ) . 2.2 The jobs associated with acetylsalicylic acid ( 1, 10 ) a. Unwanted effects GASTRIC PROBLEMS The suppression of COX 1 can bring forth stomachic perturbations as an unwanted consequence because the prostaglandin production in the GI piece of land is a homeostatic mechanism to protect the stomachic mucous membrane. It causes built-in symptoms like pyrosis ; indigestion, sickness, and abdominal hurting. ( 1, 10 ) This consequence can do Aspirin users to alter or stop it s usage. Some of these built-in symptoms are rather common for most NSAIDs. Second it can besides do gastro duodenal mucosal lesions such as erodings and symptomless ulcers, which may or may non mend spontaneously ; and eventually more serious gastro ulcers with dangerous complications like perforation, diagnostic ulcers, and shed blooding ulcers. Symptoms of this could be black, bloody, or pitch like stools or vomiting/coughing up blood REYE S SYNDROME Reye s syndrome is a aggregation of symptoms dwelling of altered consciousness, paroxysms, low blood glucose, and expansion of the liver associated with fatty infiltration of the liver. It is a deathly disease, which can strike any kid, adolescent, or grownup without warning. All organic structure variety meats are usually affected, but the liver and encephalon are antagonised the most. In 1965 it was stipulated that Reyes s syndrome can be caused by the disposal of acetylsalicylic acid in kids under 16years of age. There is no ascertained mechanism for the function of salicylate in this but it is thought that aspirin enhances the release of tumour mortification factor which induces programmed cell death of cells which can do redness, viral reproduction e.t.c. SALICYLISM This is caused by the inordinate consumption of acetylsalicylic acid. There are two chief tracts in the metamorphosis of acetylsalicylic acid. ( 10 ) Phase 1 reaction that involves the oxidization of acetylsalicylic acid to salicylic acid by a cytochrome P450 monooxygenase. By add-on of a reactive group ( OH ) to acquire it ready for junction to a soluble constituent and hence assistance elimination. This junction involves the fond regard of little polar molecules glycine and gluconoride to salicylic acid. This consequences in farther inactivation of the acetylsalicylic acid and the production of water-soluble metabolites that will be readily excreted in the piss or gall. The tract conjugated with glycine, is the 1 that is easy overloaded in instances of toxicity. Thus riddance of salicylic acid slows down and accumulation leads to a assortment of side effects. Below are the tracts demoing oxidization and junction. This extra salicylate produces toxic effects include below. Ringing in ears Hyperventilation which causes addition in CO2- respiratory alkalosis, Dehydration: increased H2O loss due to hyperventilation Loss of carbonaceous acid metabolic acidosis. This in bend will cut down the blood pH, and do aspirin return to its non-ionised signifier leting free acetylsalicylic acid in the blood watercourse. Hyperthermia. These tracts overload uncouples the energy bring forthing procedures ( oxidative phosphorylation ) of the chondriosomes therefore doing production of heat instead than ATP. Fatality particularly in kids Interactions with other drugs Decreased consequence of acetylsalicylic acid if given with isobutylphenyl propionic acid and avoid accompaniment usage of acetylsalicylic acid with NSAIDS due to increased side effects. Increase hazard of shed blooding when acetylsalicylic acid is given with coumarins, SSRIs, clopidogrel, illoprost, and sibutramine, Aspirin enhances consequence of Heparins, Phenytoin, Valporate, Aspirin antagonises consequence of Spirolactone, Sulfinpyrazone and Probenacid Rate of elimination of acetylsalicylic acid is increases by some alkalizers. The consequence of acetylsalicylic acid on the GI piece of land may be enhanced by the consumption of intoxicant and corticoids. 3. NON STEROIDAL ANTINFLAMMATORY DRUGS NON SELECTIVE COX INHIBITORS ( Christina ) 3.1 Isozymes of Cyclooxygenase Cyclooxygenase has assorted isozymes. The chief isozymes are COX-1 and COX-2, nevertheless there is now grounds of a 3rd form- COX-3. COX, originally known as prostaglandin H synthase is responsible for the oxidization of arachadonic acid to prostaglandin G2 and prostaglandin H2. It catalyses the reaction in which the arachadonic acid substrate and two molecules of O2 are converted to prostaglandin G2 and so in the perioxidase reaction Prostaglandin G2 is reduced to PGH2 by a 2 negatron decrease. The COX isozymes are heme incorporating enzymes that are homodimers. Each monomer contains three chief spheres ; A membrane binding sphere, a N-terminal cuticular growing factor sphere and a C-terminal catalytic sphere. Cyclooxygenase-1 is made up of 602 aminic acids while COX-2 is comprised of 604.3 The catalytic reaction in COX takes topographic point in a hydrophobic channel in the nucleus of the enzyme while the peroxidise reaction takes topographic point in the haem incorporating part near the surface of the enzyme. The membrane adhering sphere consists of four alpha spirals with one spiral that fuses with the catalytic sphere. These spirals congregate around an gap and through these gaps fatty acids and NSAIDS are considered to come in the active site. The COX-1 isozyme is considered a constituent enzyme. It is present in high volumes in most cells and tissues i.e. nephritic collection tubules, monocytes, endothelium etc. However COX-2 is barely noticeable in most cells, it is an inducible enzyme so it becomes more abundant in cells or tissues when macrophages are activated or by any other redness go-betweens e.g. TNF-a ( tumor necrosis factor-alpha ) or IL-1 ( interleukin-1 ) .5 Both COX-1 and COX-2 isozymes are attatched to the endoplasmic Reticulum and atomic envelope. The COX isozymes need to be N-linked glycosylated to enable them to be folded and attatched to the endoplasmic Reticulum and atomic envelope. The COX isozymes have really similar constructions for their binding site, catalytic mechanisms and produce the same biosynthetic products3 COX-3 COX-3 a 3rd isozyme was discovered in 2002 by Simmons and colleagues. They conducted a survey on Canis familiariss and this resulted in them detecting a fresh COX-1 splicing discrepancy termed COX-3 that was sensitive to acetaminophen ( paracetamol ) . It was suspected for a piece that acetaminophen worked by suppressing a different specific isozyme due to the fact that it did non straight suppress COX-1 and COX-2 really efficaciously at curative concentrations but it generated prostanoids in neural systems. 3, 15 The Simmons and colleague group showed that Datril was the existent mark for COX-3, and that it acted individually from COX-1 and COX-2. 3 Canine COX-3 is a membrane edge protein dwelling of 613 aminic acids with a molecular weight of ~65 kDa. It has a high look in cells and tissues like COX-1 proposing it may be a constituent enzyme. However the inquiry that needs to be asked is if generalizations can genuinely be made on the presence of COX-3 in worlds based on Canine surveies, so future experiments need to be designed to clear up whether a human COX-3 really does be that Acts of the Apostless independently from COX-1 and COX-2 in vivo. 14 NSAIDs are known to suppress COX in order for them to exhibit their anti-inflammatory actions, a structural NSAID binding survey was carried out. The COX-1 active site contains a long hydrophobic channel that extends from the membrane adhering sphere to the nucleus of the COX monomer. The tip of the COX active site houses Tyr385 that is located near the haem Fe. Ser530 is positioned merely below Tyr385 and that is the site for aspirin acetylation. Glu524 and Arg120 are positioned at the oral cavity of the COX-1 channel. A typical NSAID such as fluobriprofen, when introduced to the COX enzyme, its carboxylate mediety is normally directed towards the oral cavity of the COX-1 channel in order for it to be positioned in the most ideal topographic point that will let it to interact with the two polar residues Glu524 and Arg120. From these surveies a better penetration into the binding profiles of NSAIDs were observed. Non selective NSAIDs can adhere in three different ways: Reversibly ( e.g. Ibuprofen ) Fast, low affinity reversible binding followed by a higher affinity, clip dependent easy reversible binding ( e.g. fluobriprofen ) Rapid, reversible binding followed by a covalent alteration of the enzyme ( e.g. Aspirin ) 3 Arg120, Glu524, Tyr355 and His90 form a web of H bonds at the entryway of the COX channel moving like a gate to the binding site. NSAIDs by and large bind between the upper part of the COX channel near Tyr 385 and Arg 120 which is at the oral cavity of the COX channel. 3 Through the usage of H bonding and electrostatic interactions, the carboxyl mediety of acidic NSAIDs like fluoribiprofen interact with Arg120 in both COX isozymes. The important differences in the construction of the binding sites for both COX isozymes has been manipulated to enable the design of selective COX-2 inhibitors. In the COX-2 active site there is an excess accessible pocket due to the presence of a smaller valine amino acid residue at place 523 and a valine permutation at place 434, unlike COX-1, this difference increases the overall volume at the COX-2 active site by about 20 % . 1 This means that due to cut down steric and ionic crowding at the oral cavity of the channel by Arg120, not acidic selective COX-2 inhibitors can demo an enhanced and specific binding to the COX-2 enzyme. Another structural difference exists at the amino acid residue 513 where COX-1 has a histidine residue and COX-2 has an arginine mediety. 1 These little differences provides flexibleness in the substrates that can be utilised in the COX-2 active site. 3.2 Problems Associated With Non Selective Non Steroidal Anti-Inflammatory Drugs NSAIDs are one group of drugs that are on a regular basis used by the universe s population to alleviate hurting, cut down redness and lower temperature. They are COX inhibitors and act to suppress the catalysation of arachadonic acid to PGH2. COX-1 is constitutively present in most cells while COX-2 is induced by chemical go-betweens of redness and activated macrophages.13 COX-1 and COX-2 as mentioned above have 2 specific functions. The first function gives PGG2 and the other function is in the peroxidise reaction that gives PGH2. Both COX-1 and COX-2 inhibitors work by suppressing the 1st and chief function i.e. suppressing the transition of arachadonic acid to PGG2. COX-1 and COX-2 possesses hydrophobic channels within their nucleus. The classical NSAIDs exhibit their effects by barricading these enzymes halfway down the COX channel near Tyr385 and the Arg120 which is at the oral cavity of the COX channel by H bonding to the Arg120 residue. This consequences in the prohibition of any fatty acid substrates from come ining the catalytic sphere of the COX enzyme.3 In COX-1, these drugs tend to suppress the enzyme rapidly yet by and large the suppression is frequently reversible, nevertheless in COX-2 the suppression is clip dependent and frequently consequences in irreversible suppression. As mentioned before, the COX-1 and COX-2 isozyme differ somewhat. In the COX-2 active site there is an excess accessible side pocket due to the presence of a smaller valine amino acid residue at place 523 alternatively of isoleucin as in COX-1. This is of import for understanding why some Nonsteroidal anti-inflammatory are selective for the COX-2 isozyme.13 There are a figure of side effects associated with traditional NSAID therapy. NSAIDs can do nephritic failure, liver damage/disorders, sterile meningitis, skin reactions and bone marrow perturbations which can interfere with bone break healing. However amongst them all GI ( GI ) toxicities is amongst the most common. These are believed to originate from the suppression of COX-1 in the stomachic mucosa.14 GI toxicities In worlds and other species it has been shown that COX-1 non COX-2 is constitutively expressed throughout the GI tract.13 COX-1 is responsible for the synthesis of prostaglandins like PGE2 and PGI2 which are responsible for protecting the GI mucous membrane by cut downing acerb secernment in the tummy by the parietal cells, increasing blood flow in the mucous membrane and exciting the release of syrupy mucose. This leads to conditions of ulcers, indigestion, diarrhea, sickness and emesis and can even take to stomachic hemorrhage in some instances. These unwanted side effects have led to the development of COX-2 selective inhibitors. These drugs are effectual anti-inflammatory s and reflect good analgetic effects. They have considerable less stomachic harm due to the fact they selectively inhibit COX-2 with minimum action on COX-1. Unfortunately the usage of COX-2 selective drugs has been associated with increased incidence of myocardial infarction and stroke.3 Nephritic effects Prostaglandins particularly PGE2 and PGI2 are involved in modulating nephritic blood flow and vascular tone. Recent surveies have shown that COX-2 is constitutively expressed in the sunspot densa, epithelia cells run alonging the go uping cringle of henle and medullary interstitial cells of the nephritic papillae, while COX-1 is constitutively expressed in the collection canals, cringle of henle and in the vasculature. The COX-2 enzyme is associated with normal nephritic map and suppression of COX-2 consequences in NSAID-induced Na keeping while suppression of COX-1 consequences in a disease in glomerular filtration rate.3 This once and for all tells us that both COX-1 and COX-2 are involved in the physiology of the kidneys. However curative doses in patients with normal nephritic map are at small hazard of nephritic complications. It is largely newborns and the aged who are more susceptible every bit good as patients with bosom, liver or kidney disease. 4. SELECTIVE COX 2 INHIBITORS ( Nadine ) 4.1 Reasoning behind selective suppression 4.2 Benefits and hazards 5. Mechanism OF ACTION OF COX INHIBITORS IN HUMAN DISEASES 5.1 Analgesic ( Joyce ) Pain can be defined as an unpleasant sensory and emotional experience associated with existent or possible tissue harm. Pain is a self protection mechanism which helps of forces us to place danger and travel off from it. It is one of the chief symptoms used to place a status in medical specialty. Removing hurting is really indispensable in footings of either extinguishing the disease or status or in fact stamp downing its consequence. This can be done by the usage of medical specialties called anodynes. Pain receptors besides called nociceptors are present on particular nervus fibers that are sensitive to noxious of harmless stimulations. The stimulation of these receptors are on A-delta and C-fibers which are located in tegument, connective tissue, entrails, musculus e.t.c. COX inhibitors act by barricading transmittal to peripheral nervousnesss. Pain associated with I. Arthritis Arthritis is the redness of articulations. The redness and motion of the articulations cause utmost hurting in the sick person. There are two major types a. Osteoarthritis ( 10 ) This is a chronic disease that features the dislocation of the articulation s gristle. Cartilage is flexible connective tissue found in between articulations that shock absorbers or protects the terminals of the castanetss and allows easy mobility of articulations. This dislocation of gristle causes the castanetss to rub against each other making clash, doing joint tenseness, hurting and loss of mobility in the joint. There are different types of arthritis of which degenerative arthritis is most common ; it can besides be referred to a degenerative articulation disease. There are two types of degenerative arthritis, primary of which is associated with old age, general wear and tear of the gristle. And secondary where it occurs where there is a cause illustration fleshiness, injury, or hereditary. Treatment: Paracetamol may be considered as first line therapy for Osteoarthritis patients with mild to chair hurting. If the hurting does non react to paracetamol or patient has severe symptoms so other traditional NSAIDs like Ibuprofen, diclofenac or coxibs should be used. Coxibs have shown to bring forth decreased GI side effects. However they have the chance of increasing cardiovascular hazard because they inhibit prostacyclin production in endothelial cells but non thromboxane in thrombocytes, therefore this can increase the opportunity of a thrombus formation. The pick of a coxib or a specific NSAID should be based on the patient features and hazard factors. b. Rheumatoid arthritis ( 12 ) This is an autoimmune disease of unknown beginning whose major feature is the redness and eroding of the synovial membrane or synovial membrane. This membrane lines and surrounds the joint and synovial pit. The synovial membrane secretes a somewhat syrupy, clear fluid known as synovial fluid, which lubricates pit that lies between the gristle and articulation on the bone. In Rheumatoid arthritis accretion of the synovial fluid builds up within the joint infinite and causes redness. This makes the joint expression and experience conceited. Rubor occurs do to the increased blood flow to the country because of redness. In conditions of long-run RA, joint devolution can happen doing mobility to be really painful and restricted. Treatment: Aspirin used to be used to handle RA but because of its GI toxicity. The usage of acetylsalicylic acid as first line of therapy has been superceded by other NSAIDs. There are a big figure of NSAIDs that have been invented since acetylsalicylic acid, but have similarities in toxicities e.g. Ibuprofen, naproxen meloxicam, etodolac selective COX-2 inhibitors have been invented to command redness. These drugs were designed to battle the GI hazard of NSAIDS, but there are concerns of additions in cardiovascular hazard. II. Cancer ( 11 ) Can be defined as an unnatural growing of cells as when a group ofcellsdisplayuncontrolled division, invasion, and sometimesmetastasis. Cells become malignant neoplastic disease cells because of its damaging consequence to the Deoxyribonucleic acid of the cell. A normal cell will seek to mend damaged Deoxyribonucleic acid but in a malignant neoplastic disease cell it replicates with the damaged DNA. The malignant neoplastic disease cell continues doing new cells that the organic structure does non necessitate. The most common cause of malignant neoplastic disease hurting is infiltration of the tumor into bone. Bone metastases occur as a effect of different types of malignant neoplastic disease. Another mechanism of pain apart from bone metastasis is the secernment of Prostaglandins by carcinomas. For this ground, NSAIDs should be included in any regimen to command hurting associated with bone metastasis. Because NSAIDs do non trip opioid receptors, they can supply extra hurting alleviation when combined with an opioid anodyne. Therefore, uniting an Nonsteroidal anti-inflammatory with an opioid anodyne may supply equal hurting control with a clinically important decrease in opioid dosage. This opioid-sparing consequence of NSAID therapy allows the clinician to decrease the side effects associated with opioid therapy without giving hurting control. Coxibs: Another Option for Cancer Pain Management ( 11 ) The recent debut of the coxibs, on their usage in malignant neoplastic disease patients is still being studied. Oncologists are replacing NSAIDs, with the usage of coxib, because of the improved safety profile compared to traditional agents. Surgical oncologists are researching the usage of coxibs both preoperatively and during the post-operative period to cut down opioid use in order to rush the recovery procedure 5.2 Anti-pyretic ( Nadine ) 5.3 Anti-inflammatory ( Christina ) To day of the month there are over 100 inflammatory diseases- each of which causes the devolution of connective tissue in one or more parts of the organic structure. These include: Rheumatoid Arthritis Osteoarthritis Atherosclerosis Cranky Bowel Disease Alzheimers diseases and many more. Inflammation is characterised by dolour, inflammation, calor and tubor, it s one of the organic structure s ways of reacting to harmful stimulations, pathogens, hurt or disease. These normally initiate an ague or chronic inflammatory response. Arthritis is a general term used to characterize redness in the articulations. Rheumatoid arthritis describes arthritis that occurs on both sides of the organic structure i.e symmetrical. These normally occur in the carpuss, custodies and articulatio genuss. It is non known what causes this disease many theories have been put frontward but it happens when the immune system begins to assail the articulations. A figure of anti-inflammatory drugs are available worldwide and are widely used to alleviate hurting, swelling and redness associated with soft tissue redness. A figure of these drugs act via the suppression of COX. When you experience hurting and redness from arthritis, an addition in microvascular permeableness occurs selectively in post-capillary venulas. The endothelial cells undergo conformational alteration taking to vascular escape through spreads between the next endothelial cells. At the site of hurt scavenger cells are attracted and travel into the affected tissue along with plasma. The plasma causes the associated swelling observed in redness and the scavenger cells engulf dead cells and bacteriums. Prostanoic acids are produced via the metamorphosis of fatty acids through the COX tract. When you have pain from arthritic arthritis or any other inflammatory disease these damaged cells release prostaglandins which are really of import go-betweens in the symptoms associated with redness such as swelling and pain.15 The COX enzyme plays an of import function in the synthesis of prostanoic acids from arachadonic acids. There are 2 COX isozymes in the organic structure. COX-1 mediates cellular procedures and produces prostanoic acids, while COX-2 is mediated by proinflammatory cytokines. Cox inhibitors such as NSAIDs exhibit their effects by suppressing the first measure in the biosynthetic tract of change overing arachadonic acid to PGG2 hence forestalling the synthesis of PGH2.16 This helps to cut down the hurting, swelling and redness caused by the disease nevertheless it does nt decelerate down or extinguish the patterned advance of the disease. 5.4 Anti-platelet activity ( Omolara ) Blood curdling is an of import physiological procedure that prevents inordinate hemorrhage from happening. However, sometimes inappropriate coagulum formation occurs within the blood vas and this is known as thrombosis. A thrombus/clot impairs blood flow and can take to complete obstruction of the vas therefore ensuing in cardiovascular diseases such as myocardial infarction, shot and deep vena thrombosis. The primary map of thrombocytes is to understate blood loss after tissue injury by organizing a coagulum at the site of the injured vas. However, the boundary line between the physiological hemostasis and the patho-phsiological response which causes thrombosis is really narrow. Thromboxane A2 ( TxA2 ) is a labile prostanoid that is synthesised by activated thrombocytes via consecutive reactions of COX and thromboxane synthase enzymes.23 Atherosclerosis is a chronic disease of the vasculature in which plaques build up on the interior of the arterias. It is influenced by multiple factors which include blood constituents and the nature of the arterial wall. TxA2 is known to advance the induction and coevals of atherogenesis by commanding thrombocyte activation. Research has shown that thrombocytes are to some extent responsible for the pathological development of atherothrombosis, of which there is an increasing mortality rate in the developed world.25 One of the most of import physiological actions of zxA2 is platelet activation which allows thrombocytes to alter their form, sum and therefore leads to thrombosis and thrombin formation. Aspirin has been shown to suppress thrombus formation mediated by TxA2-induced thrombocyte collection and vascular bottleneck which sometimes causes acute myocardial infarction and intellectual infarction.23 Thus, the suppression of thrombocyte collection is the footing for the intervention of cardiovascular diseases. This is most normally achieved by suppressing the COX-1 isoform in thrombocytes which is responsible for the synthesis of the of import thrombocyte agonist thromboxane ( TxA2 ) from Arachidonic acid.22 Arachidonic acid is the precursor for prostaglandin biogenesis and it is a 20 C unsaturated fatty acid which is embedded in cell membranes as a phospholipid ester. In the organic structure, Arachidonic acid is released in response to assorted stimulations and this free Arachidonic acid is converted to assorted lipid go-betweens which are jointly known as eicosanoids via COX, lipoxygenase and CYP450.3 PGH2 is converted by assorted cell specific isomerases and synthases in order to bring forth 5 biologically active prostaglandins which include PGD2, PGE2, PGF2, PGI2 and TxA2. With regard to the anti-platelet action of acetylsalicylic acid and other COX inhibitors the focal point will be on PGI2 and TxA2. In thrombocytes, the COX-1 isoform is constitutively expressed and is responsible for the production of thromboxane ( TxA2 ) . The synthesis of prostacyclin ( PGI2 ) in endothelial cells is catalysed chiefly by the COX-2 isoform. PGI2 has an opposite consequence to TxA2 as it inhibits thrombocyte collection ( anti-aggregatory ) .3 Aspirin, which is known to be effectual in cut downing the hazard of farther cardiovascular jobs acts as an irreversible inhibitor of COX-1 in thrombocytes. It acetylates the Ser530 found between the positively charged Arg120 which is situated at the oral cavity of the COX channel, and a profoundly buried Tyr385 that initiates the cyclo-oxygenation of arachidonate ( See Figure 3 ) . Aspirin irreversibly binds to the active site and for good blocks the entry of arachidonate to the active site. This consequences in the abolition of thromboxane ( TxA2 ) synthesis within thrombocytes every bit good as the vascular endothelial synthesis of the antithrombotic PGI2 ( prostacyclin ) due to the fact that acetylsalicylic acid is a non selective COX inhibitor. 3 However, unlike endothelial cells thrombocytes are anucleate and are unable to replace the inactivated COX enzyme. As a consequence the synthesis of TXA2 is prevented for the full life-time of the platelet.1 A low dosage of acetylsalicy lic acid ( 75mg ) has a more effectual anti-platelet activity because higher concentrations are required to suppress endothelial COX coevals than thrombocyte COX generation.3 The irreversibility of this interaction and the alone look of COX-1 in anucleate thrombocytes are responsible for the curative advantage of acetylsalicylic acid against thrombosis.26 As established by current clinical guidelines, Aspirin has been successfully over the decennaries for this intent and is frequently routinely given to patients with any arteriosclerotic disease.22 Research has shown that acetylsalicylic acid remains an effectual inhibitor of thrombocyte map when given on a long term low day-to-day doses to cardiovascular patients.24 During the survey of the interaction between acetylsalicylic acid and the COX-1 active site, it was discovered that although aspirin H bonds with Arg120 and acetylates Ser530, Tyr385 is critical for this acetylation. This was confirmed by the site directed mutant of Tyr385 to phenylalanine in which the action of acetylsalicylic acid was reduced by over 90 % . The function of Tyr385 is to stabilise the negatively charged tetrahedral intermediate that is formed during acetylation and this increases aspirins activity. The carbonyl O of the acetyl adduct forms a H bond with the phenolic H of Tyr385. The acetyl group on Ser530 protrudes into the COX-1 active site instantly below Tyr 385, which causes the closing of the top of the channel. Hence, substrate entree to the catalytic tyrosyl group is prevented.1,24 Due to the fact that acetylsalicylic acid has proven to be effectual irreversible inhibitor of COX-1 in thrombocytes, medicative chemists are looking into the research of acetylsalicylic acid parallels. A pharmacophore demonstrates how the place of single hydrophilic/hydrophobic group is critical for successful interaction ; it deals with the indispensable functional group that interacts straight with the active site and the spacial agreement. As discussed earlier, aspirin inhibits COX-1 enzyme by interacting with Arg385 or Tyr385 leting its bringing of its ethanoyl group group to Ser530. However, the construction has non been optimised to suit the active site. Having looked at the pharmacophore and the indispensable functional groups have been identified some compounds have been synthesised and tested for anti-platelet activity.24 The construction shown supra is a fresh acetylsalicylic acid parallel which was found to suppress platelet collection on experimental survey. It contains an ester group which can at the same time interact with Arg120 and Tyr385 at the COX-1 active site whilst positioning its ethanoyl group group close to Ser530. Unlike acetylsalicylic acid this ester derived function is non acidic and may be utile as a lead compound for farther development of COX inhibitors with anti-platelet activity.24 Aspirin is the lone clinically used COX inhibitor that irreversibly inactivates COX-1 and this involves a alteration of the COX active site which is clip dependent. It is able to this amongst all other COX inhibitors because it forms strong covalent bonds with the active site. In footings of the binding to the COX activex site, acetylsalicylic acid is the least potent of the clip dependent COX inhibitors as it has a low affinity for the active site and this is reflected by its remarkably high k1 value ( k1=20mM ) . However, one time acetylsalicylic acid is bound to the active site acetylation of Ser530 progresses rapidly.1 Although acetylsalicylic acid is a non selective COX inhibitor it does non hold an equal authority on the COX isozymes. It is 10-100 times more powerful against COX-1 compared to COX-2 and selectively marks platelet COX-1 in the pre-systemic circulation therefore giving aspirin its cardiovascular benefits. However, these benefits may be compromised when acetylsalicylic acid is administered together with other NSAIDs. Human and in vitro surveies have shown that isobutylphenyl propionic acid and indomethacin prevent acetylsalicylic acid from being able to demobilize thrombocyte COX-1. Celecoxib and Vioxx which are extremely selective COX-2 inhibitors have been shown to hold no intervention with the anti-platelet activity of acetylsalicylic acid in healthy human topics have been shown. The consequences of these clinical surveies have shown that the ability of NSAIDs and selective COX-2 inhibitors to interfere with the consequence of acetylsalicylic acid relates with their repressive au thority against COX-1. Those that have a low affinity for COX-1 and a high COX-2 selectivity will demo a low potency to barricade the anti-platelet effects of aspirin.1 Acetylation of Ser-530 by aspirin consequences in a gt ; 95 % suppression of the ability of thrombocytes to bring forth TXA2 throughout the 24hr dosing period. This complete and uninterrupted suppression is of import for the cardio-protective effects of acetylsalicylic acid because of the inexistence of a additive relationship between the suppression of thrombocyte mediated TXA2 production and the suppression of TXA2 mediated platelet collection. Bantam concentrations of TXA2 have been shown to do thrombocyte activation and so it can be concluded that a gt ; 95 % suppression of platelet COX-1 activity is needed in order to accomplish an consequence on thrombocyte map. Epidemiologic surveies have shown that other NSAIDs which cause uncomplete and intermittent suppression of thromboxane biogenesis may be uneffective in forestalling cardiovascular events. However, in vitro surveies have shown Naproxen ( curative dosage 500mg twice daily ) to be effectual in suppressing platelet COX-1 activity ( gt ; 95 % ) .27 Naproxen is an interesting NSAID which shows alone adhering dynamicss with COX-1 and COX-2. It displays neither authoritative clip dependent suppression nor competitory suppression. Naproxen has the ability to suppress COX easy and reversibly as opposed to NSAIDs that quickly and reversibly suppress COX e.g. isobutylphenyl propionic acid and others that inhibit COX in a slow and functionally irreversible mode. It is thought that this may be partially responsible for the possible cardio-protective effects of Naprosyn noted in clinical tests. Besides human surveies have shown that Naprosyn can mime the anti-platelet consequence of low dosage acetylsalicylic acid, nevertheless naproxen is non used clinically for this purpose.1 6. Future APPLICATIONS OF COX INHIBITORS IN THE TREATMENT OF HUMAN DISEASES ( Zaneta ) The epoch of NSAIDs begun at the terminal of Nineteen century. It was non know until 74 old ages after the mechanism of action of first COX inhibitor, acetylsalicylic acid, was appreciated1. Since so other types of COX inhibitors came to visible radiation with a focal point on cut downing GI side effects of non-selective COX inhibitors and cardiovascular inauspicious effects due to selective COX-2 inhibitors3. Expression of both enzymes within the organic structure differs. COX-1 is expressed chiefly in tissues such as endothelium, thrombocytes, monocytes, nephritic collection tubules, seminal cysts, GI piece of land and cringle of Henle whereas COX-2 in inflammatory and malignant neoplastic disease tissues associated with endothelium, osteoclasts, synovial tissues, monocytes, macrophages, sunspot densa in the uriniferous tubule, go uping cringle of Henle and the encephalon 1,3. There are several studies indicating at different applications of usage of COX inhibitors like in malignan t neoplastic disease bar and/or supressive interventions with one meriting wider attending. Recent surveies demonstrated that overexpression of COX-2 influences tumour growth6. In add-on some findings besides suggest that the usage of COX-2 inhibitors could profit in bar of cancerous cells formation6. The research by Spugnini et Al ( 2007 ) concluded that COX inhibitors could potentially be of pick in the intervention for Mesothelioma, a signifier of malignant neoplastic disease that affects body pits peculiarly the pleura and serosal surfaces6. They proposed that since action of COX enzyme during prostanoids synthesis trades with formation of extremely reactive species i.e. groups ( Fig.1. ) potentially taking to DNA harm. More over since prostaglandins formed take portion in mitogenesis, suppression of programmed cell death and programmed cell decease intercession within either consequence could convey promising consequences towards tumor suppression. Although COX inhibitors are o f possible intervention in Mesothelioma the survey concluded that there is still limited attack towards possible intervention because it was proven merely in vitro studies6. Nevertheless, uniting anticancer drugs along with COX inhibitors might convey more effectual intervention with higher rate of endurance. 7. CONCLUSION ( Omolara ) Without uncertainty, COX inhibitors have proven to be really utile in the intervention of human diseases by cut downing the hurting and redness associated with medical conditions. The chief COX inhibitors are the NSAIDs. Aspirin a non selective COX inhibitor was described by some as a A ; lsquo ; wonder drug and is besides known to hold anti-platelet effects at low doses. However, due to their known side effects some of their utilizations are questionable particularly the selective COX-2 inhibitors of which some have been withdrawn from the market. In most human diseases, COX inhibitors will necessitate to be taken on a long term footing therefore their safety profile is merely every bit of import as their clinical efficaciousness. The unchallenged efficaciousness of COX inhibitors has led to current and future researches being geared towards their usage in malignant neoplastic disease prophylaxis and bone healing. 8. Mentions Blobaum A.L and. Marnett L.J, ( 2007 ) A ; lsquo ; Structural and Functional Basis of Cyclooxygenase Inhibition , Journal of Medicinal Chemistry 50 ( 7 ) pp 1425-1441. Science Direct [ Online ] . Available at: hypertext transfer protocol: //www.sciencedirect.com ( Accessed 2009 ) . Tsai. A and Kulmacz R.J ( 2009 ) A ; lsquo ; Prostaglandin H synthase: Resolved and unsolved mechanistic issues , Archivess of Biochemistry and Biophysicss Praveen Rao P.N and Knaus E.E ( 2008 ) A ; lsquo ; Evolution of Nonsteroidal Anti-Inflammatory Drugs ( NSAIDs ) : Cyclooxygenase ( COX ) Inhibition and Beyond , Journal of Pharmacy and Pharmaceutical Science, 11 ( 2 ) pp 81s-110s. Science Direct [ Online ] . Available at: hypertext transfer protocol: //www.sciencedirect.com ( Accessed 24 August 2009 ) . Kulmacz R.J. , Van der Donk W.A. and Tsai A.L. ( 2003 ) A ; lsquo ; Comparison of the belongingss of prostaglandin H synthase-1 and -2 , Progress in Lipid Research. 42 ( 5 ) pp 377-404. Science Direct [ Online ] . Available at: hypertext transfer protocol: //www.sciencedirect.com ( Accessed 2009 ) . Botting R. M. ( 2006 ) A ; lsquo ; The Cyclooxygenase: Past, nowadays and hereafter. A testimonial to John R. Vane ( 1927-2004 ) , Journal of Thermal Biology. 31 ( 1-2 ) pp 208-219. Science Direct [ Online ] . Available at: hypertext transfer protocol: //www.sciencedirect.com ( Accessed 2009 ) . Spugnini E.P, Citro G. and Baldi A. ( 2007 ) A ; lsquo ; Cox Inhibitors as Potential Chemotherapic Drugs for Mesothelioma , Current Respiratory Medicine Reviews. 3 ( 1 ) pp 15-18. Science Direct [ Online ] . Available at: hypertext transfer protocol: //www.sciencedirect.com ( Accessed 2009 ) . Rinsema T.J ( 1999 ) A ; lsquo ; One hundred old ages of acetylsalicylic acid , Medical History. 43 ( 4 ) pp 502-507. Pubmed cardinal [ Online ] . Available at: hypertext transfer protocol: //www.ncbi.nlm.nih.gov/pmc/ . ( Accessed 2009 ) Vane J.R. and Botting R.M. ( 2003 ) . A ; lsquo ; The mechanism of action of acetylsalicylic acid , Thrombosis research. 110 ( 5-6 ) pp 255-258. Science Direct [ Online ] . Available at: hypertext transfer protocol: //www.sciencedirect.com ( Accessed 2009 ) Morita I. ( 2002 ) A ; lsquo ; Distinct maps of COX-1 and COX-2 , Prostaglandins A ; other Lipid Mediators 68-69 pp165-175. Science Direct [ Online ] . Available at: hypertext transfer protocol: //www.sciencedirect.com ( Accessed 2009 ) Vonkeman H. E. and. Van de Laar M A.F.J ( 2008 ) A ; lsquo ; Nonsteroidal Anti-Inflammatory Drugs: Adverse Effectss and Their Prevention . Seminars in arthritis and rheumatism. Science Direct [ Online ] . Available at: hypertext transfer protocol: //www.sciencedirect.com ( Accessed 2009 ) Laine L. , Rostom A. , Hochberg M. and Stevenson D.D ( 2008 ) COX-2 Selective Inhibitors in the intervention of Osteoarthritis. Seminars in arthritis and rheumatism. 38 pp 165-187Science Direct [ Online ] . Available at: hypertext transfer protocol: //www.sciencedirect.com ( Accessed 2009 ) Ruoff G. and Lema M. ( 2003 ) A ; lsquo ; Schemes in Pain Management: New and Potential Indications for COX-2 Specific Inhibitors . Journal of Pain and Symptom Management. 25 ( 2S ) pp 21-31 Gonzalez-Gay M.A. , Gonzalez-Juanatey C. and Martin J. ( 2005 ) . A ; lsquo ; Rheumatoid Arthritis: A Disease Associated with Accelerated Atherogenesis , Seminars in arthritis and rheumatism. 35 ( 1 ) pp 8-17. C. Patrono, B. Rocca. ( 2009 ) Nonsteroidal anti-inflammatory drugs: Past, nowadays and hereafter. Pharmacological Research. Vol 59 Issue 5 pg 285-289 S. Bancos, M P Bernard, D J Topham and R P Phipps. ( 2009 ) Ibuprofen and other widely used non-steroidal anti-inflammatory drugs inhibit antibody production in human cells. Cellular Immunology. Vol 258 Issue 1 pg 18-28 J M Schwab, H J Schluesener, R Meyermann and C N Serhan. ( 2003 ) COX-3 the enzyme and the construct: stairss towards extremely specialized tracts and preciseness therapeutics? Prostaglandins, leukotrienes and indispensable fatty acids. Vol 69 Issue 5 pg 339-343 L Laine, W B White, A Rostom and M. Hochberg. ( 2008 ) COX-2 selective inhibitors in the intervention of degenerative arthritis. Seminars in Arthritis and Rheumatism. Vol 38 Issue 3 pg 165-187. M.Capone, S. Tacconelli, L. Di Francesa et. Al. ( 2007 ) Pharmacodynamic of Cox inhibitors in worlds. Prostaglandins and other lipid go-betweens. Vol 82 Issue 1 pg 85-94 K. Abouzid, S. Bekhit. ( 2008 ) Novel anti-inflammatory agents based on pyridazinone scaffold ; design, synthesis and in vivo activity. Bioorganic A ; Medicinal Chemistry. Vol 16 Issue 1 pg 5547-5556 R. Rao, S. Meena, A. Rao. ( 2005 ) An overview of the recent developments in analytical methodological analysiss for finding of COX-2 inhibitors in majority drugs, pharmaceuticals and biological marices. Journal of pharmaceutical and Biomedical Analysis. Vol 39 Issue 1 pg 349-363 H. Suleyman, E. Cadirci, A. Albayrak, Z. Halici. ( 2008 ) Nimesulide is a selective COX-2 inhibitory, untypical non-steroidal anti-inflammatory drug. Current Medicinal Chemistry. Vol 16 Issue 1 pg 278-283 C. Blatteis. ( 2006 ) Endotoxic febrility: New constructs of its ordinance suggest new attacks to its direction. Pharmacology A ; Therapeutics. Vol 111 Issue 1 pg 194-223 Galliard-Grigioni K.S. , Fehr M. , Reinhart W.H. ( 2008 ) . A ; lsquo ; Influence of combinations of acetylsalicylic acid, Datril, and diclofenac on thrombocyte collection . European Journal of Pharmacology. 595 pp65-68. Science Direct [ Online ] . Available at: hypertext transfer protocol: //www.sciencedirect.com ( Accessed 10 November 2009 ) Norimichi N. ( 2008 ) . A ; lsquo ; Thromboxane A2: Physiology/pathophysiology, cellular signal transduction and pharmacological medicine . Pharmacology A ; Therapeutics, 118 pp18-35. Science Direct [ Online ] . Available at: hypertext transfer protocol: //www.sciencedirect.com ( Accessed 2 November 2009 ) Alagha A. , Moman E. , Adamo M.F. , Nolan K.B. , Chubb A.J. , ( 2009 ) A ; lsquo ; Design, synthesis and rating of acetylsalicylic acid parallels holding an extra carboxylate substituent for antithrombotic activity . Bioorganic A ; Medicinal Chemistry Letters 19 p4213-4216 Science Direct [ Online ] . Available at: hypertext transfer protocol: //www.sciencedirect.com ( Accessed 15 November 2009 ) Rivera J. , Lozano M.L. , Navarro-N A ; uacute ; A ; ntilde ; ez L. , Vicente V. ( 2009 ) A ; lsquo ; Platelet receptors and signaling in the kineticss of thrombus formation . Haematologica 94 ( 5 ) Haematologica [ Online ] . Available at: hypertext transfer protocol: //www.haematologica.org ( Accessed 24 October 2009 ) FitzGerald G.A. , Loll P. , ( 2001 ) A ; lsquo ; COX in a crystal ball: current position and future promise of prostaglandin research . The Journal of Clinical Investigation ; 107 ( 11 ) 1335-1337 Pub Med Central [ Online ] . Available at: hypertext transfer protocol: //www.ncbi.nlm.nih.gov/pmc/ ( Accessed 24 November 2009 ) Capone M.L. , Tacconelli S. , Di Francesco L. , Sacchetti A. , Sciulli M.G. , Patrignani P. , ( 2007 ) . A ; lsquo ; Pharmacodynamic of Cox inhibitors in worlds . Prostaglandins A ; other Lipid Mediators 82 p85-94 Science Direct [ Online ] . Available at: hypertext transfer protocol: //www.sciencedirect.com ( Accessed 16 November 2009 ) Parente, L. and Perretti, M. ( 2003 ) . A ; lsquo ; Progresss in the pathophysiology of constituent and inducible Coxs: two enzymes in the limelight . Biochemical Pharmacology 65 ( 2 ) 153-159 Available at: hypertext transfer protocol: //www.sciencedirect.com ( Accessed November 2009 ) Rouzer, C.A. and Marnett, L.J. ( 2005 ) . A ; lsquo ; Structural and functional differences between Coxs: Fatty acid oxygenases with a critical function in cell signalling . Biochemical and Biophysical Research Communications 338 34-44 APPENDIX ( Group part )

Essays on Curriculum Development Essays

Essays on Curriculum Development Essays Essays on Curriculum Development Essay Essays on Curriculum Development Essay I will critically analyse and evaluate Functional skills English and GCSE English [N2] [N3]You should start by providing a definition of curriculum have a look in the study guide  The Functional Skills curriculum develops practical skills in English. It is a new qualification available to all learners aged 14 and above. Functional Skills English is not just about knowledge in English, it is about knowing when and how to use the knowledge in real life situations. Functional Skills English involves taking separate tests in speaking and listening, reading and writing which will give you a qualification if you pass them, giving you skills for life in english. They will also count towards other qualifications, including Diplomas and Apprenticeships, these are available in schools, colleges, training providers and the workplace. Functional Skills English is now part of the secondary school curriculum and is currently being piloted in a three-year scheme since 2010 along side GCSEs. During this time, the qualifications are being offered on their own at Entry Level, Level 1 and Level 2 on the National Qualifications Framework. Functional skills may be linked to the ideology of Progressivism, meeting individuals needs and aspirations so as to support their personal growth and strengthen a democratic society. This approach developed by John Dewey in the earlier 20th century was based around active problem solving in a variety of social contexts and encouraging people to learn how to think for themselves, make decisions and participate in a democratic society which now days would be the use of functional skills. (www.wakeypedia.org.uk)[N4]  Functional skills in practical terms explains that at level 2 in English, students are able to write something with accurate grammar, punctuation and spelling, and where the meaning is clear. GCSEs are the main qualification taken by 14 to 16 year olds in the UK, but are available to anyone who would like to study a subject that interests them. You can take GCSEs in a wide range of academic and work-related subjects. GCSE stands for General Certificate of Secondary Education. Its highly valued by schools, colleges and employers, so will be useful whatever you are planning to do in the future. The GCSE curriculum may be linked to the ideology of Instrumentalism: having an highly skilled and educated workforce that will meet the needs of international competition and values high levels of literacy. The instrumental curriculum sees knowledge in factual terms and is clearly lecturer/teacher/trainer led. Through this method students are prepared for the workplace and society in general. In relation to school leavers, having a GCSE in english to seek employment once leaving school is deemed as the norm. GCSEs are usually studied full-time at school or college, taking five terms to complete. A percentage of their final grade will be from course work produce as a portfolio.  For an English GCSE you must take an exam in English literature and an exam in English language, there is a choice of two tiers: higher or foundation. Each tier leads to a different range of grades. Your subject teacher normally decides which tier is best for you.  GCSEs were revised, so that from 2010, they are supposed to test thoroughly functional skills. If students fail to achieve level 2 in this test, they can not exceed a grade D at GCSE. If English GCSEs are not about functional skills, then what are they about? If students can pass English GCSE without being able to write clearly, such as writing a letter, or if they can pass Maths without being able to do everyday applied maths tasks such as working out their family budget then the curriculum has no validity. [N5](www.news.bbc.co.uk) states Mike Baker.  The Qualifications and Curriculum Authority began defining functional skills, producing a 52-page booklet intended as a helpful guide to the new tests. This explains that the level of functional skills will depend on the complexity of situations and activities, the technical demand associated with those activities, a learners level of familiarity with the task, and the level of independence with which they can complete the task.([N6]www.news.bbc.co.uk) So pupils can still get their GCSEs without passing a functional skills test first. Can we be sure that, from 2010, achieving a grade C in English or Maths GCSE will prove a student is functionally literate or numerate.  It will be interesting to see how many students getting Cs or above at GCSE also pass the functional skills level 2 tests which is deemed to be equivalent to a grade A-C GCSE. Without passing this test they would not be able to gain a grade C in these exams. If students can pass English GCSE without being able to write clearly, surely something is wrong. Mike Baker (2009)  FEEDBACK: These last few paragraphs read like a conclusion. However, although this is interesting you havent made it relevant to the task. Your conclusion needs to sum up what you did in the essay and what you discovered and briefly state any opinions, such as, which curriculum you think is better.

MacDonalds CSR Strategy Essay Example | Topics and Well Written Essays - 750 words - 1

MacDonalds CSR Strategy - Essay Example Examined in this essay are factors influencing the implementation of MacDonald’s CSR strategies and the current aspirational goals contained in the corporation’s â€Å"2020 CSR and Sustainability Framework† launched in 2014.   MacDonald’s CSR strategy remains reputable with other corporations operating in the same niche mirroring their strategies. The company’s ultimate goal entails the reduction of environmental impact of its operations. In addition, the company aims to ensure sustainability whereby, they emphasize on human well-being, energy efficiency and animal health. In the case of the latter, they support entrepreneurs whose animal rearing projects encompass sustainable production. In the fiscal year 2012-2013, the company sourced 100% whitefish from certified fisheries verified by agencies for using sustainable means of production. In addition, the company installed approximately 300,000 energy-efficient kitchen equipment in different outlets (2014). The rampant rise in obesity and the increase in environmental degradation played a pivotal role in influencing MacDonald’s CSR strategies. Wihbey (2012) estimated that the rate of obesity among male adults is 32.2% whereas, that of women is 35.5%. In addition, obesity in the country costs the government an estimated $ 190 billion in medical expenses (Whibey, 2012). Poor dietary habits and leading a sedentary lifestyle are the major causes of obesity in the US. Therefore, companies operating in the fast food industry must be accountable for decreasing the rampant rise in obesity in the country. Intervention strategies implemented by the government continues to compel companies such as MacDonald’s to implement their own CSR strategies that help decrease the rate of obesity. For example, the use of more organic products in the preparation of their meals, and the provision of healthier alternatives to soft drinks (bypasses the soda tax while ensuring a healthy alternative f or customers). Conversely, increased environmental pollution across the globe also compelled MacDonald’s to re-assess their sourcing strategies, packaging materials, and energy consumption in their different outlets.  

Why Franchising is Going Global Assignment Example | Topics and Well Written Essays - 500 words - 33

Why Franchising is Going Global - Assignment Example Social structures – the structures within the international market differ from those within the US. Consideration of these factors will enable the franchises to effectively undertake operations within the global market. The business operations of the franchises must become integrated with the social structures within those countries. Cultural values and attitudes – in seeking to satisfy the new customers which the franchise will get in the international market, understanding the customers becomes essential. A consideration of these elements becomes essential in managing the cultural diversity which is created through the expansion of the franchise into the international market. The attitudes and values will be essential in the development of strategies aimed at marketing the franchise to the international market. In seeking to enhance the appropriateness of franchise products within the international market the franchises must undertake different approaches. These appro aches will be aimed at ensuring the products match with the demands of the new international market. The franchises would be required to undertake the following activities. Evaluate the country’s economic system in seeking to ensure the utilization of business operations which are appropriate to the economic system. The franchises must undertake research within the country in which the franchise will operate in order to understand the operational elements which must be present for successful business operations. This would enable the franchises to learn about the various laws and regulations existing within the country, and the source of business supplies(Pipes, 2014). Understanding these factors will present the franchises with the capacity to undertake business operations successfully and ensure the appropriateness of their products. This study will enable the franchises to implement effective business strategies which are based on the situation analysis of the various elem ents which govern business operations within the other countries.

Christianity and mathematics Essay Example for Free

Christianity and mathematics Essay This paper deals with interrelation between Christianity and mathematics. It has been observed that God is the creator of this universe and He is also the creator of our various mathematical formulae and deductions. Like Universe and God, they are also eternal and cannot be ever destroyed. The paper has also described how Christianity has described the relation between God and our numeric system, which is the basic foundation of Mathematics. Christianity and mathematics 3 Link between Christianity and mathematics – philosophical aspect Let us consider the formulae for earths mass distribution, orbital path of celestial bodies and population fluctuation. They are simple mathematical formulae that describe the creation of this universe and humanity. According to Christianity, who is the creator of this Earth? It is none than the God himself. Jonathan Zderad (2003) has stated in the article written in the website http://www. acmsonline. org/Zderad-creationism. pdf that universe, that is the creation of God is hardwired by the laws of mathematics. If one have a look at the theorems of mathematics, it seemed that they were true before time began and will continue to be true after time lapses. Jonathan has mentioned this in his article in the above mentioned website. Mathematics exists beyond human thought and logic. Christianity believes that only God can create such things which are eternal and divine. Jonathan (2003) has mentioned in his article that mathematics existed beyond time and space. According to Christianity, only God, the supreme power behind this human existence can exist beyond time and space. It is very much clear from the Biblical records that god gives value to numbers. To quote from the above mentioned website, â€Å"For Christians, God’s counting is what gives the believer a place in heaven. Jesus compared himself to a shepherd who leaves the ninety-nine sheep to rescue one sheep that is lost. He values each and every one of us. † (p. 6). Jonathan Zderad (2003). The Holy Bible has drawn many references from the numeric system of mathematics. How Christianity is linked to basic numeric system of mathematics Jonathan (2003) has also described in the above mentioned article how Christianity is Christianity and mathematics 4 related to our numeric system. The author has described that while the Number represents unity, number 2 is the symbol of fellowship and number 3 representing the community. The author states that these numbers represent spiritual qualities. The author has stated in the article that Bible has enough indications that it is God who has created the series of integers, rational and irrational numbers and real numbers. Jonathan has argued in the article that Bible has strong reference to the concept of counting. Numbers were generally used to describe dimension while building a place of worship. How Creation of God is linked with creation of mathematics The author has also suggested in the above article that there is a clear view of Christian view of Mathematics, which is described as creationism. Creationism has got four aspects. The first one is continuity. God makes his own creation in such a way that it is continuous. The second aspect is activity. The author has stated that he has created all these mathematical entities out of his own mental divine activities. The third one has been described as the abstract object inclusive. To quote, â€Å"As a general rule, theists would include mental objects and spiritual objects in the list of God’s invisible creation. Creationism also includes abstract objects like propositions, relations, and universals in this list of God’s invisible creation†. (p7). Jonathan Zderad (2003). The fourth one is that it is mathematically inclusive. It believes that Mathematical objects are created by God and they have an eternal quality, which can only proceed from the mind of God. Christianity and mathematics 5 Reference Zderad, Jonathan. (2003) Creationism – A Viable Philosophy of Mathematics. www. acms. org. Retrieved on 15th December, 2008, from http://www. acmsonline. org/Zderad-creationism. pdf

Transformation of Rev. Arthur Dimmesdale in Hawthornes The Scarlet Let

The Scarlet Letter:   The Transformation of Rev. Dimmesdale "Life is hard, but accepting that fact makes it easier." This common phrase clearly states a harsh fact that Rev. Dimmesdale, a character in Nathaniel Hawthorne's The Scarlet Letter, had to face. In this story of deception and adultery set in the Puritan era, Hawthorne introduces Dimmesdale as a weak and cowardly man who refuses to take responsibility for his actions.   The Rev. Dimmesdale is a transitional character in that he is, at the beginning of the novel, outwardly good but inwardly deceitful and by the end of the novel he becomes both outwardly and inwardly truthful.   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   At the beginning of the novel, Dimmesdale has established quite a reputation for himself.   In discussing individual members of the magistrate, the towns people describe Dimmesdale as a "God fearing" gentleman, "but merciful overmuch (49)". Due to his actions all of the people respect and look up to the Reverend.   Throughout the story, Dimmesdale desperately tries to confess, envying Hester, for her courage, he says, "Happy are you Hester, that wear the scarlet letter openly upon your bosom† (188)!   Even at the end of the novel, when finally attempting to confess, people are compelled by his final sermon, raving that "never had a man spoken in so wise, so high, and so holy a spirit, as he that spake this day† (243).  Ã‚   Proving that he was a very loved and influential man in the small town.   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   In further developing Dimmesdale's character, Hawthorne portrays him as a hypocrite.   His outward demeanor deceives the villagers, appearing as a completely holy man.   However, before the action of the novel begins, he stumbles into sin, by committing adultery with Hester Pryn... ...and a character other than Dimmesdale could not have painted such a vivid, and memorable picture in one's mind.    1.  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   Great thesis statement !!! 2.  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   Your conclusion paragraph should be more detailed. Restate in just a few sentences the points that you made in your paper and what conclusions you have drawn from those points. 3.  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   When quoting, the parentheses, which hold the page number, should come after the quotation marks and the punctuation should come after the parentheses.   An example of a correctly cited quote would be â€Å"A spell was broken† (251). Instead of â€Å"a spell was broken (251)†. 4.  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   Also be careful of run-on sentences.   Let your sentences contain only one or two ideas, not three or four.   Do not over-use semicolons or colons, use a period instead. Transformation of Rev. Arthur Dimmesdale in Hawthorne's The Scarlet Let The Scarlet Letter:   The Transformation of Rev. Dimmesdale "Life is hard, but accepting that fact makes it easier." This common phrase clearly states a harsh fact that Rev. Dimmesdale, a character in Nathaniel Hawthorne's The Scarlet Letter, had to face. In this story of deception and adultery set in the Puritan era, Hawthorne introduces Dimmesdale as a weak and cowardly man who refuses to take responsibility for his actions.   The Rev. Dimmesdale is a transitional character in that he is, at the beginning of the novel, outwardly good but inwardly deceitful and by the end of the novel he becomes both outwardly and inwardly truthful.   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   At the beginning of the novel, Dimmesdale has established quite a reputation for himself.   In discussing individual members of the magistrate, the towns people describe Dimmesdale as a "God fearing" gentleman, "but merciful overmuch (49)". Due to his actions all of the people respect and look up to the Reverend.   Throughout the story, Dimmesdale desperately tries to confess, envying Hester, for her courage, he says, "Happy are you Hester, that wear the scarlet letter openly upon your bosom† (188)!   Even at the end of the novel, when finally attempting to confess, people are compelled by his final sermon, raving that "never had a man spoken in so wise, so high, and so holy a spirit, as he that spake this day† (243).  Ã‚   Proving that he was a very loved and influential man in the small town.   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   In further developing Dimmesdale's character, Hawthorne portrays him as a hypocrite.   His outward demeanor deceives the villagers, appearing as a completely holy man.   However, before the action of the novel begins, he stumbles into sin, by committing adultery with Hester Pryn... ...and a character other than Dimmesdale could not have painted such a vivid, and memorable picture in one's mind.    1.  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   Great thesis statement !!! 2.  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   Your conclusion paragraph should be more detailed. Restate in just a few sentences the points that you made in your paper and what conclusions you have drawn from those points. 3.  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   When quoting, the parentheses, which hold the page number, should come after the quotation marks and the punctuation should come after the parentheses.   An example of a correctly cited quote would be â€Å"A spell was broken† (251). Instead of â€Å"a spell was broken (251)†. 4.  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   Also be careful of run-on sentences.   Let your sentences contain only one or two ideas, not three or four.   Do not over-use semicolons or colons, use a period instead.

Old English Lyrical Poetry Essay

The second part allegorically represents that the troubles of the seaman are the troubles of earthly life and the call of the ocean is the call in the soul to go to its true home with God.The poem is remarkable for (as Legouis puts) – â€Å"The somber and violent pictures it gives of northern seas in which sufferings from cold mingles with the pains of water and wind†. The Ruined Burg or the Ruin:- * It is an elegy not for the misfortune of a person but for a place. * The unknown poet laments for the vanished glory of a great city, probably the Roman built city Bath, which was turned into debris by the Anglo-Saxon aggression, Conquest and settlement. * The poem can be divided in three parts- ) First the poet describes the ancient gorgeous buildings now deserted and rootless and tottering. b) Next he goes to muse on its golden past and its adorned and crowded noble princess and warriors. c) Finally he contrasts the runions present with the pompous past. * The poem is rem arkable for its nostalgic melancholy and for its descriptive nature. Deor’s Lament: * It is a poem of 42 lines, divided into stanzas and it is included in the Exeter Book. * It is the lamentation of Deor, a scop who after years of service has been supplanted by another minstrel, Herrenda. Finally he consoles himself by considering the misfortune of others. * It is written in strophic form throughout and each strophe ends with a refrain. * There are altogether seven sections in the poem. * In the first five sections, the mentions the adversities that befall others but ends with a note of consolation in the sixth section he speaks of the misfortune of mankind in general. And in the seventh section the poet mentions his own misfortune. In this way the poem is logically well-knit.It remains plainly heathenic in sentiment. The Wife’s Complaint: * It is a kind of monologue. * The narrator is a woman whose husband has left her and gone to the sea. She is forced to live in an old dwelling dug out of earth under oak by her husband’s relatives. She sitting under the tree laments over her miserable lot all day. Friendless and fore shaken she bewails her loneliness and the vows of love that have come to nothing. * The poem is rich in melancholy feeling. The Husbandà ¢â‚¬â„¢s Message: * It exists in fragments. A good many lines of this poem are lost for ever. * An exiled husband sends his message to his wife by means of letters carved on a piece of wood. The wood tells the wife its own life story and its journey in a ship. It tells her that though the circumstances let her husband out of home he has been able to gain a position of wealth and dignity. Finally it bids her to join with her husband in the place of exile. * To some critics the poem is a sequel to ‘The Wife’s Complaint but some would to see it as an independent poem.

Electric Field

Name ____________________________________Electric Fields Go to http://phet. colorado. edu/simulations/sims. php? sim=Electric_Field_Hockey and click on Run Now. 1. You rub balloons in your hair and then hang them like in the picture below. Explain why you think they move apart and what might affect how far apart they get. A balloon becomes negatively charged when it is rubbed on a person’s hair.This occurs because all the protons and neutrons leave the balloon and attach to other objects such as the hair. If two balloons both have negative charges then both balloons will repel each other because same charges repel while opposites attract. 2. Test your ideas using Electric Field Hockey in the Practice mode. Make a table to record your observations about what affects the direction and speed of the puck. Your table should demonstrate that you have run controlled tests with all the variables. Charges introduced |Effects on positive charge repulsion | |Positive |Repel | |Negative |Attract | Charges introduced |Effects on positive charge speed | |Positive |Close to charge=Increasing repulsion speed | | |Far from charge= decreasing repulsion speed | |Negative |Close to charge=Increasing attraction speed | | Far from charge= decreasing attraction speed | 3. Reflect on your ideas from question #1 and your data from question #2. How do your observations support, dispute or add to your ideas about what affects how charged bodies interact? The data collected helps support my claims that like charges repel each other while opposites attract. In the case of the balloons both balloons are negative there for repelling each other. 4. As you put charges onto the playing area, arrows appear on the puck. †¢ What do you think the arrows on the puck are illustrating?The arrows illustrate the movement of the pucks as well as velocity. †¢ How do the arrows from the positive charges compare and contrast to the ones from the negative balls? The positive charges seem to repel the puck while the negatives attract. †¢ Investigate how you can use the arrows to predict the motion of the puck. 5. Write an explanation of how you can predict the motion of a charged hockey puck that is moved by other charged pucks. Explain using examples and drawings that include: †¢ How to use free body diagrams and vector addition. †¢ How negative and positive charges compare and contrast.

Abortionagainst essays

Abortionagainst essays In 1973, through the ruling of Roe vs. Wade, abortion was made constitutionally legal for all women in the United States. Since then, our country has been divided on this issue. The statement, Id like young women to understand that abortion is not the ultimate answer. The answer is in counseling and Christian fellowship (qtd. in Wood 43), was made by Norma McCorvey Roe of the Roe vs. Wade judgment. McCorvey fought for the right to have an abortion. She was victorious which led to legalized abortion in the United States. She deeply regrets that decision and now lectures against abortion. Moreover, some say that the choice of having an abortion should exclusively be the womans decision, therefore it should be legal, while others say that it is the murdering of an innocent life and should be outlawed. The latter is the appropriate decision. The only exception that should be considered is that the survival of the mother or baby is not guaranteed. If the mother or child have no chance of survival, an abortion should be an option for the pregnant woman. Consequently, the major debate amongst the opposing sides is the definition of life, or when a human life begins. Pro-choice, or pro-abortion debaters say that only when a baby is born, it begins life as a human. The opposing pro-life view believes that human life begins at conception, when the egg is fertilized by the sperm. According to science, once the egg is fertilized every characteristic of a brand-new human being is existent, even the color of the eyes, hair, the sex and everything else. There is truth in the statement, Pregnancy is the period for this new human life to mature, not to become human...it already is. (McDonagh 92). Abortion is the the destruction of an unborn baby. Women know that what grows inside of them is not just a group of cells. They know from the beginning what is inside. Women grieve...

The Biography of Louise McKinney

The Biography of Louise McKinney A temperance advocate, Louise McKinney was one of the first two women elected to the Alberta Legislative Assembly and one of the first two women elected to a legislature in Canada and in the British Empire. An excellent debater, she worked on legislation to help people with disabilities, immigrants, and widows and separated wives. Louise McKinney was also one of the Famous Five Alberta women who fought and won the political and legal battle in the Persons Case to have women recognized as persons under the BNA Act. Birth September 22, 1868, in Frankville, Ontario Death July 10, 1931, in Claresholm, Northwest Territories (now Alberta) Education Teachers College in Ottawa, Ontario Professions Teacher, temperance and womens rights activist and Alberta MLA Causes of Louise McKinney temperance educationstronger liquor controlwomens property rights and the Dower Act Political Affiliation Non-Partisan League Riding (Electoral District) Claresholm Career of Louise McKinney Louise McKinney was a teacher in Ontario and then in North Dakota.She moved to a homestead near Claresholm, Northwest Territories in 1903.Louise McKinney became involved in the Womans Christian Temperance Union (WCTU) while in North Dakota and organized a chapter in Claresholm. She continued as an organizer for the WCTU for more than 20 years, eventually becoming acting president of the national organization.Louise McKinney was elected to the Alberta Legislative Assembly in 1917, in the first election in which Canadian women could run for office or vote. Suspicious of the political donations made by large brewing and liquor companies to the major parties, Louise McKinney ran under the banner of the Non-Partisan League, an agrarian movement.With the help of Henrietta Muir Edwards, Louise McKinney introduced the bill that became the Dower Act, which guaranteed a woman a third of the family estate when her husband died.Louise McKinney was defeated in the 1921 Alberta election and did no t run again. Louise McKinney was one of four women to sign the Basis of Union forming the United Church of Canada in 1925.Louise McKinney was one of the Famous Five Alberta women in the Persons Case which established the status of women as persons under the BNA Act in 1929.

Animal Make Us More Human Essay Example | Topics and Well Written Essays - 750 words

Animal Make Us More Human - Essay Example Naturally children, when left to their own devices, will take the first step and form activities and other stories in the world which is around them. With children who have passed their toddler age, most imaginative games and plays begin because of parental guidance or supervision. Unstructured free play takes place in many varying environments, but, the outdoors may give more chances for free play because of movable items, such as dirt, sticks, rocks, leaves, which provide them with the opportunity of creation and exploration. Some parents do not find it easy to give unstructured play time for the kids. Giving kids time without continuous supervision and guidance, in particular outside play, is difficult. It feels difficult to find reasonable concern, over-attention and the yearning to get kids familiar with freedom and learned from their own experiences and mistakes. Emotional intelligence and socialization is increased through physical movement and shared interactions. Children also work together to come up with what game they have to play and then agree the rules and how to deal with scenarios that always involve the varying perspectives of all. These works they do together build in the social qualities that everyone want for their kids. Children are building with self-awareness, compassion, empathy, flexibility and self-regulation. This emotional development is endorsed with the physical health as kids playing outside move a lot. In children and adults alike the level of physical activity has been well recognized to reduce the anxiety, stress and despair and to enhance the overall mood. This research is thin in young adults and youngest kids get the most advantage as well. Free play in young children and toddlers most often involves the burst of gross motor activity over a time period with numerous ones over a time period. Most of the children are laughing

Subprime Recent Events Essay Example | Topics and Well Written Essays - 1000 words

Subprime Recent Events - Essay Example According to this theory, no government across the globe will allow any big financial institution or a bank to collapse so easily. This is because the after effect or the consequences of such collapses would definitely be great and at time will be out of control to handle despite how big the economy in which the collapse occurred. This exactly is the basic reason as to why AIG was bailed out by the U.S. Federal Reserve. The reasons substantiated by the U.S. Federal Reserve as to why it took this step of bailing out AIG was it felt that the collapse of such a big financial institution would definitely add to the woes of the financial markets and economy which is currently delicate. The Fed also stated that the collapse of AIG would also result in higher cost of borrowings, reduction in the household wealth and also weaken the current performance of the economy. It was also true that the collapse of AIG would not only effect the U.S. economy alone as felt by the Fed but would also have a drastic and negative impact on the global financial markets. Now, the important and popular question that is prevailing in the global markets is to why has Fed bailed out only AIG and not the other financial institution that collapsed during the same time i.e. ... If the scenario or the case of Lehman Brothers' is observed, the company was having problems with its financial situation for almost more than a year now i.e. since the year 2007, one year even before the company bankrupted. In the month of August 2007, the company closed one its subprime lenders. As a result of this the company recorded a onetime post-tax charge of approximately $25 millions. This scenario did not end there. The same kind of situation continued even in the year 2008 when the company wrote down a huge number of its subprime mortgage securities. These write downs of the company's subprime mortgage securities as accounted by the company were a $2.8 billion loss in the second quarter. If the company's financial position or the various situations of the company were looked for the period of January to June of the year 2008, the value of stock loss of the company can be equated to almost 75% (IPC'sIntelligent Investor, 2007). These happenings in the company and its stock position or value itself acted as a sign of caution to its investors. To be specific, as the scenario of financial troubles at Lehman Brothers' was happening for almost one year and as investors knew what was happening in the company and also the decrease in the stock value, it would have been a clever idea to pull out the fund from such a company or at least look at alternatives to save their investments which most of the in vestors of Lehman Brothers' did not do. This alone can be mentioned as a reason behind the U.S. Federal Reserve's move of bailing out AIG and letting off Lehman Brothers'. Similarly, if the scenario at AIG is observed, the financial trouble or crisis occurred all of a sudden in the company. The collapse of Lehman Brothers also would have