Cyclo-oxygenase inhibitors of human diseases

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 Butazolidin ( 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.

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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 allowed 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 biosynthesis5.

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.


2.1. 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

  2. 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

  4. 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.

  6. 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.

  1. Ringing in ears
  2. Hyperventilation which causes addition in CO2- respiratory alkalosis,
  3. Dehydration: increased H2O loss due to hyperventilation
  4. 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.
  5. Hyperthermia. These tracts overload uncouples the energy bring forthing procedures ( oxidative phosphorylation ) of the chondriosomes therefore doing production of heat instead than ATP.
  6. 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.


3.1 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 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.


4.1 Reasoning behind selective suppression

4.2 Benefits and hazards


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



Cranky Bowel Disease

Alzheimer’s 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 n’t 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 acetylsalicylic 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 authority 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


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 malignant 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 of 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

  1. 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: // ( Accessed 2009 ) .
  2. Tsai. A and Kulmacz R.J ( 2009 ) & A ; lsquo ; Prostaglandin H synthase: Resolved and unsolved mechanistic issues ‘ , Archivess of Biochemistry and Biophysicss
  3. 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: // ( Accessed 24 August 2009 ) .
  4. 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: // ( Accessed 2009 ) .
  5. 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: // ( Accessed 2009 ) .
  6. 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: // ( Accessed 2009 ) .
  7. 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: // . ( Accessed 2009 )
  8. 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: // ( Accessed 2009 )
  9. 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: // ( Accessed 2009 )
  10. 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: // ( Accessed 2009 )
  11. 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: // ( Accessed 2009 )
  12. 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
  13. 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.
  14. C. Patrono, B. Rocca. ( 2009 ) Nonsteroidal anti-inflammatory drugs: Past, nowadays and hereafter. Pharmacological Research. Vol 59 Issue 5 pg 285-289
  15. 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
  16. 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
  17. 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.
  18. 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
  19. 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
  20. 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
  21. 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
  22. 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
  23. 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: // ( Accessed 10 November 2009 )
  24. 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: // ( Accessed 2 November 2009 )
  25. 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: // ( Accessed 15 November 2009 )
  26. 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: // ( Accessed 24 October 2009 )
  27. 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: // ( Accessed 24 November 2009 )
  28. 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: // ( Accessed 16 November 2009 )
  29. 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: // ( Accessed November 2009 )
  30. 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
  31. APPENDIX ( Group part )

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Cyclo-oxygenase inhibitors of human diseases. (2017, Sep 02). Retrieved from

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