Non-steroidal Anti-inflammatory Drugs: Mechanisms of Action

Non-steroidal Anti-inflammatory Drugs: Mechanisms of Action Non-steroidal anti-inflammatory drugs are a type of drugs that can be used as pain killers. Nowadays, other pain killers such as paracetamol are more widely used, as they have fewer side effects, and cost less. However, NSAIDs are mostly used in conditions which cause inflammation. It may take from a few days to more than three weeks to show their anti-inflammatory effects. They are specifically used to treat arthritis, menstrual cramps, sports injuries, and headaches. There are different types of NSAIDs that are used in different situations. For example, Ketorolac (Toradol) is only used for short-term treatment of moderately severe acute pain that otherwise would be treated with opioids. (Ogbru, 1997). Aspirin is also a NSAID that is used long-term, at low doses, specifically to inhibit blood clot formation and prevent heart attacks and strokes in individuals at high risk for developing blood clots. The most common and undesirable side effects of NSAIDs are nausea, vomiting, diarrhoea, decreased appetite, constipation, rash, dizziness and headache. The most severe side effects are kidney failure, liver failure, ulcers and prolonged bleeding after an injury or surgery (Ogbru, 1997). Mechanisms of Action Prostaglandins are a group of lipid compounds that are produced by specific group of enzymes called cyclooxygenases from arachidonic acid (Zeilhofer, 2007), which promote vital functions in inflammation, pain, fever; support the blood clotting function of platelets; and protect the lining of the stomach from the damaging effects of acid (Ogbru, 1997) (Figure 1). Mode of action of NSAIDs is to exert anti-inflammatory, analgesic (pain relieving), and antipyretic (fever-reducing) effects through the blockade of prostaglandin synthesis via non-selective inhibition of cyclooxygenases (COX-1 and COX-2) isozymes (Chakraborti et al., 2010). Both COX-1 and COX-2 enzymes produce prostaglandins that serve inflammation, pain and fever. However, only COX-1 produces and regulates prostaglandins that protect the stomach (gastrointestinal) and support platelets (Ogbru, 1997) (Figure 2). NSAIDs reduce the concentration of prostaglandins throughout the body by blocking the COX enzymes. As a result of this, ongoing inflammation, pain and fever are decreased. For example, when concentration of prostaglandin E2 (PGE2) elevates in certain parts of the brain, body temperature increases. This increase in body temperature changes the firing rate of neurons that control thermoregulation in the hypothalamus. Aspirin which can act as an antipyretic, work by inhibiting the enzyme cyclooxygenase and reducing the levels of PGE2 within the hypothalamus of the brain. As a consequence, body temperature falls, and fever is relieved (Aronoff Neilson, 2001). It is important to understand that the pain pathway is not the same for fever and other cases like tissue injuries. In tissue injury, prostaglandins together with other agents like histamine, act on the sensory neurons present in the injured or stimulated tissue which in turn conduct the generated signal to the spinal cord. The afferent fibres (neurons) transmit the pain signal to the spinal cord. The signal is then propagated from the spinal cord to the pain centres in brain. This is carried out by synapse formation between afferent sensory neuron in the dorsal root ganglion of the spinal cord, transferring the signal up the spinothalamic tract to synapse in the thalamus. Therefore the final synapse with the primary sensory cortex fibres occurs in the thalamus (Lorne, 2010) (Figure 3 4). As a result of this, pain centres in brain will become alerted and body will feel the pain. Therefore, prostaglandin synthesis inhibition by NSAIDs will result in pain pathway blockage, hence reduc ing or killing the pain. Irrespective of the type of injured tissue (ligament, tendon or muscle), the body reacts to injury with a sequence of events that initiates with an influx of inflammatory cells and blood. Removal of debris and recruiting growth factors e.g. cytokines toward the injury site are the subsequent events that are carried out by the inflammatory cells. The same Prostaglandins that are blocked by NSAIDs are partly involved in this inflammatory stage. In a normal healing process (without application of NSAIDs), a proliferative stage consisting of a mixture of fibroblasts and inflammatory cells naturally follows the inflammatory stage. At this stage, the fibroblasts construct a new extracellular matrix and continue into the maturation stage (final stage) where functional tissue is laid down. The crucial point is that each stage of repair is a prerequisite for the subsequent stage. Hence, although blocking the inflammatory stage by NSAIDs relieves the pain, it may delay the healing of musculosk eletal injuries (Stovitz Johnsons, 2003). Side effects of NSAIDs such as ulcers and bleeding promotion are due to reduction in bodys prostaglandin level which protects the stomach and supports platelets and blood clotting. In other words, NSAIDs like aspirin, especially in high doses, act as pain killers by reducing prostaglandin concentration; however, this reduction can also raise severe unwanted effects like ulcers (Ogbru, 1997). There are various NSAIDs in terms of potency, duration of action, body elimination manner, how strongly they inhibit COX-1 and their tendency to cause ulcers or promote bleeding. The more an NSAID blocks COX-1, the greater is its tendency to cause ulcers and promote bleeding. One NSAID,  celecoxib  (Celebrex), blocks COX-2 but has little effect on COX-1, and is therefore further classified as a selective COX-2 inhibitor. Selective  COX-2 inhibitors  cause less bleeding and fewer ulcers than other NSAIDs. (Ogbru, 1997). Rofecoxib (tradename = Vioxx) In 1999, two new highly selective COX-2 inhibitors, known as coxibs (celecoxib and rofecoxib) which were claimed to have low gastrointestinal (GI) side effects were introduced which resulted in high commercial development. Rofecoxib (Vioxx) was introduced by Merck (one of the largest pharmaceutical companies) as a more effective and a safer alternative to NSAIDs for the treatment of pain associated with osteoarthritis (Krumholz et al., 2007). While found to have fulfilled these goals in part, a worrying series of events took place in the late 2004 period when rofecoxib was withdrawn worldwide from the market because of alarming cardiovascular incidents and concerns about increased risk of heart attack and stroke due to long-term, high-dosage use. Other coxibs were subsequently withdrawn on suspicion of having the same adverse effects, although to a varying degree (Rainsford, 2007). Previous to introducing the drug to the market, it were concerned that the drug might have adverse effects on the cardiovascular system by changing prostacyclin to thromboxane ratio, which have opposite effects on regulating blood flow and clotting. (Prostacyclin and thromboxane are members of the family of lipids known as eicosanoids.) (Krumholz et al., 2007) A study sponsored by Merck during 1996-1997 reported that rofecoxib decreased the concentration of prostacyclin metabolites in urine in healthy volunteers by about half. Merck officials sought to soften  the academic authors interpretation that COX-2 inhibition within the vascular endothelium may increase the propensity for thrombus formation, the basis of what became  known as the FitzGerald hypothesis. The academic authors changed  the manuscript at Mercks request-for example, they changed  systemic biosynthesis of prostacyclin was decreased by  [rofecoxib] to Cox-2 may play a role in the systematic biosynthesis  of prostacyclin. (Krumholz et al., 2007). However, despite knowing that rofecoxib may elevate thrombus formation, none of the studies that constituted Mercks new drug application to the Food and Drug Administration (FDA) in 1998 were designed to examine cardiovascular risk. The studies were all generally small, had short treatment periods, enrolled patients at low risk of cardiovascular disease, and did not have a standardised procedure to collect cardiovascular results (Krumholz et al., 2007). In 1999, the largest study on rofecoxib, the vioxx gastrointestinal outcomes research (VIGOR), took place by Merck. The purpose of the study was to show that the drug would have fewer GI side effects than naproxen (NSAID) for the treatment of rheumatoid arthritis. The study took place without a standard procedure for collecting information on cardiovascular events. Finally, the study showed that rofecoxib was not more effective in terms of mitigating symptoms of arthritis but halved the risk of GI events. However, the study showed that there was also evidence of an increased risk of myocardial infarction. Therefore, the first suspicion about the metabolite meanings i.e. urine prostacyclin data was right. Nevertheless, Merck decided to propose a naproxen assumption, implying that rofecoxib had not been harmful but that naproxen had been protective, despite having no evidence that naproxen had a protective effect on cardiovascular system (Krumholz et al., 2007). Finally, after wide usage of Vioxx in clinical centres around the world for around 5 years, due to an increase in serious cardiovascular events, the company voluntarily withdrew Vioxx from the market, in 2004. Currently, a lot of studies are taking place to discover why cardiovascular failures took place with coxibs, to identify safer coxibs, and to clarify the roles of COX-2 and COX-1 in cardiovascular diseases and stroke in order to develop newer agents to control these conditions (Rainsford, 2007). Overall, in order to improve the care of patients and gain their trust back, putting patients interests first is necessary. A renewed commitment and re-establishing collaborations between industry, academics, journals and practising doctors are the only way to extract something positive from this unfortunate event.

Break Room Rules and Regulations

In our effort to give more comfort to our employers, we are presenting this new break room that can be used by every employee during their lunch time or other free times. To be able to maintain its cleanliness and orderliness, we make some guidelines on using it. This memo contains the rules and regulation on using the said room.1. This room is made for all the employees only. Inviting some guests or visitors is discouraged. 2. Please be reminded that you are not alone in this room. Doing something that may disturb other employees is strictly prohibited.3.  Smoking is prohibited because it may affect the health of others. 4. Posting a note on the wall is prohibited. There will be a place provided to you to put your note. 5. Be sure to clean up all the food wrappers, tissues, dirty dishes every time you finish your meal.Please be reminded that there are some employees that will use the room after you. 6. The refrigerator is for food storage only. Storing things, except for food, is strictly prohibited. 7. Please use garbage cans to avoid dirty environment. This will make the room more pleasant in the eyes of every employee.Violators of these rules are subjected to any punishments according to what intense of the violation made. These rules and regulations are open for suggestion and any comments. References Haworth inc. Office etiquette 101 Retrieved on August 28, 2007 from http://sourcebook. haworth. com/websourcebook/content/items/document/e1062. pdf American Bar Association (2007). Office Etiquette Essentials. Retrieved on August 28, 2007 from http://www. abanet. org/media/youraba/200704/article12. html New York Magazine Holdings (2007). Codes and Conduct. Retrieved on August 28, 2007 from http://nymag. com/guides/2007/officelife/30012

How to Improve Your Vocabulary

There are many ways to improve your vocabulary. When working to do so, its important to know your goals in order to best choose the way in which you want to learn. For instance, reading can be a great way to improve your vocabulary, but it wont be much help on a vocabulary test next week. Here are a number of methods to help you improve and expand your English vocabulary. Synonyms and Antonyms A synonym is a word that has a similar meaning. An antonym is a word that has the opposite meaning. When learning new vocabulary, try to find at least two synonyms and two antonyms for each word. This is especially important when learning adjectives or adverbs.   Use a Thesaurus A thesaurus is a reference book that provides synonyms and antonyms. Used by writers to help find just the right word, a thesaurus can also help English learners expand their vocabulary. You  can use an  online thesaurus  which makes finding a synonym easier than ever. Vocabulary Trees Vocabulary trees help provide context. Once youve mapped out a few vocabulary trees, youll discover yourself thinking in vocabulary groups. When you see a cup your mind will quickly relate such words as knife, fork, plate, dishes, etc.   Create Vocabulary Themes Create a list of vocabulary themes and include a definition and an example sentence for each new item. Learning by theme emphasizes words that are related. This will help you memorize new vocabulary because of the connections between these words and your chosen theme. Use Technology to Help You Watching movies or sitcoms is a great way to help you understand native speakers of English. Use the  options of watching individual scenes to make DVD use into a vocabulary learning exercise. For example, watch one scene from a movie in English only. Next, watch the same scene in your native language. After that, watch the same scene in English with subtitles. Finally, watch the scene in English without subtitles. By watching the scene four times and using your own language to help, youll pick up a lot of idiomatic language. Specific Vocabulary Lists Rather than studying a long list of unrelated vocabulary, use specific vocabulary lists to help you prepare for the type of vocabulary you need for work, school, or hobbies. These business vocabulary word lists are great for industry-specific vocabulary items. Word Formation Charts Word formation refers to the form a word takes. For example, the word satisfaction  has four forms: Noun: satisfaction --  The satisfaction of a job well done is worth the effort.Verb: satisfy -- Taking this course will satisfy your degree requirements.Adjective: satisfying / satisfied  -- I found the dinner very satisfying.Adverb: satisfyingly -- His mother smiled satisfyingly as her son won the award. Word formation is one of the keys to success for advanced level ESL learners. Advanced level English exams such as the TOEFL, First Certificate CAE, and Proficiency use word formation as one of the key testing elements. These word formation charts provide the concept noun, personal noun, adjective, and verb forms of key vocabulary listed in alphabetical order. Research  Specific Positions A great place to start learning vocabulary for a specific job is the Occupational Outlook Handbook. At this site, you will find detailed descriptions of specific positions. Use these pages to take note of key vocabulary related to the profession. Next, use this vocabulary and write your own description of your position.   Visual Dictionaries A picture is worth a thousand words. Its also very helpful for learning precise vocabulary. There are a number of excellent English learner visual dictionaries for sale. Here is an online version of a visual dictionary dedicated to jobs. Learn Collocations Collocations refer to words that often or always go together. A good example of a collocation is  do your homework.  Ã‚  Collocations can be learned through the use of corpora.  Corpora  are huge collections of documents that can track the number of times a word is used.  Another alternative is to use a collocation dictionary. This is especially helpful when focusing on business English. Vocabulary Learning Tips Use vocabulary learning methods to focus quickly on the vocabulary YOU need to study.  Dont make random lists of new words. Try to group words in themes. This will help you memorize new words more quickly.Always add context by writing out  a few example sentences using new vocabulary.  Keep a vocabulary notepad at hand whenever you are reading in English.Use a flashcard app on your smartphone to review vocabulary when you have some extra time.  Before you begin your day, choose five words and try to use each word during conversations throughout the day.