Pharmacophore of COX-inhibitor

Under supervision:

Dr.Mohammed Taha

AUTHERD BY

• Ahmed Mohammed Abdo• Eslam Mohammed Farag• Abdelraoof Khalifa Ahmed• Abdalla Saad Zaghloul• Mohammed Hanfy• Mahmoud Sayed Mohammed• Mohammed Jaber Mohammadeen• Ahmed Abdalla Rabea Ahmed• Emad Ali Abdelhamid• Hossam Eldein Mohammed Zaki

Cyclooxygenase (COX)

• Known as : prostaglandin-endoperoxidesynthase (PTGS).

• that is responsible for formation of prostanoids:

1. Prostaglandins

2. Prostacyclin

3. Thromboxane.

• involved in the inflammatory response.

Cyclooxygenase (COX)

• Contains two separate active sites for prostaglandin synthase

1. One side contains the cyclooxygenase active site

2. The opposite side contains the peroxidaseactive site which is involved in activating the heme group necessary for cyclooxygenase reaction

• Has two forms, COX1 and COX2.

COX-1

• Continuously stimulated by the body

• Constitutive (Its concentration in the body remain stable)

• Creates prostaglandins used for basic house keeping throughout body

• Prostaglandins stimulate normal body functions such as stomach mucous production, regulation of gastric acid and kidney water

Cox 2

• Induced ( normally not in present in cells)

• Built only in special cells (EX : lung cells)

• Used for signaling pain and inflammation

• Produces prostaglandins for inflammatory response

• Stimulated only as part of immune response

• Production is stimulated by inflammatory cytokines and growth factors

COX:

Selective cox-2 inhibitor

CELECOXIB

CelecoxibSynthesis of Celecoxib:

N-(trifluoroacetyl)imidazole + acetophenone 1,3-dicarbonyl adduct. 1,5-diarylpyrazole

Mechanism of Action:• Celecoxib is a nonsteroidal anti-inflammatory drug that exhibits anti-inflammatory,

analgesic, and antipyretic activities . The mechanism of action of Celecoxib is believed to be due to inhibition of prostaglandin synthesis, primarily via inhibition of cyclooxygenase-2 (COX-2), and at therapeutic concentrations in humans, Celecoxib does not inhibit the cyclooxygenase-1 (COX-1) isoenzyme.

• In colon tumor models, Celecoxib reduced the incidence and multiplicity of tumors.

Celecoxib

• IUPAC Name:

4-[5-(4-methylphenyl)-3(trifluoromethyl)pyrazol-

1-yl]benzenesulfonamide

• Drug name: CELEBREX

Celecoxib

• Absorption• Peak plasma levels of celecoxib occur approximately 3 hrs after an oral

dose. Under fasting conditions, both peak plasma levels (Cmax) and area under the curve (AUC) are roughly dose proportional up to 200 mg BID; at higher doses there are less than proportional increases in Cmax and AUC .

• Absolute bioavailability studies have not been conducted. With multiple dosing, steady state conditions are reached on or before Day 5.

• Distribution• In healthy subjects, celecoxib is highly protein bound (~97%) within the

clinical dose range. In vitro studies indicate that celecoxib binds primarily to albumin and, to a lesser extent, α1-acid glycoprotein. The apparent volume of distribution at steady state (Vss/F) is approximately 400 L, suggesting extensive distribution into the tissues.

• Celecoxib is not preferentially bound to red blood cells.

Celecoxib

• Metabolism• Celecoxib metabolism is primarily mediated via cytochrome P450. Three metabolites:1. a primary alcohol.2. the corresponding carboxylic acid and its glucuronide conjugate, have been identified in human

plasma. These metabolites are inactive as COX-1 or COX-2 inhibitors. 3. Patients who are known or suspected to be P450 poor metabolizers based on a previous history

should be administered celecoxib with caution as they may have abnormally high plasma levels due to reduced metabolic clearance.

• Excretion• Celecoxib is eliminated predominantly by hepatic metabolism with little (<3%) unchanged drug

recovered in the urine and feces. • The primary metabolite in both urine and feces was the carboxylic acid metabolite (73% of dose)

with low amounts of the glucuronide also appearing in the urine. • The effective half-life is approximately 11 hours under fasted conditions. • The apparent plasma clearance (CL/F) is about 500 mL/min.

Celecoxib

• Side effet:

• chest pain, shortness of breath.

• coughing up blood.

• nausea, upper stomach pain, itching ,jaundice (yellowing of the skin or eyes).

• skin rash, muscle weakness; or severe skin reaction ,skin pain, followed by a red or purple skin rash that spreads (especially in the face or upper body) and causes blistering and peeling.

ROFECOXIB

Rofecoxib

• Synthesis of Rofecoxib:

phenylacetic acid

butenolide

triflate4-bromothioanisoleorganoboric acid

Rofecoxib

• IUPAC Name:

• 3-(4-methylsulfonylphenyl)-4-phenyl-2H-furan-5-one

• Drug name: VIOXX

Rofecoxib

• Mechanism of Action• Rofecoxib selectively inhibits the cyclooxygenase-2 (COX-2) enzyme,

important for the mediation of inflammation and pain. Unlike non-selective NSAIDs, Rofecoxib does not inhibit platelet aggregation.

• ABSORPTION• The mean oral bioavailability of Rofecoxib at the rapeutically

recommended doses of 12.5, 25, and 50 mg is approximately 93%. • The median time to maximal concentration (Tmax), as assessed in nine

pharmacokinetic studies, is 2 to 3 hours. Individual Tmax values in these studies ranged between 2 to 9 hours. This may not reflect rate of absorption as Tmaxmay occur as a secondary peak in some individuals.

• With multiple dosing, steady-state conditions are reached by Day 4. • Rofecoxib Tablets 12.5 mg and 25 mg are bioequivalent to Rofecoxib Oral

Suspension 12.5 mg/5 mL and 25 mg/5 mL, respectively.

Rofecoxib

• DISTRIBUTION• Rofecoxib is approximately 87% bound to human plasma protein over the

range of concentrations of 0.05 to 25 mcg/mL. The apparent volume of distribution at steady state (Vdss) is approximately 91 L following a 12.5-mgdose and 86 L following a 25-mg dose.

• METABOLISM• Metabolism of Rofecoxib is primarily mediated through reduction by

cytosolic enzymes.• Cytochrome P450 plays a minor role in metabolism of rofecoxib. Inhibition

of CYP 3A activity by administration of ketoconazole 400 mg daily does not affect Rofecoxib disposition. However, induction of general hepatic metabolic activity by administration of the non-specific inducer rifampin600 mg daily produces a 50% decrease in rofecoxib plasma concentrations.

Rofecoxib

• EXCRETION• Rofecoxib is eliminated predominantly by hepatic metabolism with little (<1%)

unchanged drug recovered in the urine. • The plasma clearance after 12.5- and 25-mg doses was approximately 141 and 120

mL/min, respectively.• Higher plasma clearance was observed at doses below the therapeutic range,

suggesting the presence of a saturable route of metabolism (i.e., non-linear elimination). The effective half-life (based on steady-state levels) was approximately 17 hours.

• Side effect:• More common: • Congestion in chest ,Cough ,fever, sneezing, sore throat• Less common :• burning feeling in chest or stomach ,chills ,hives ,loss of appetite ,muscle aches

and pain ,prolonged or severe vomiting ,shortness of breath ,skin rash ,tenderness in the stomach area ,vomiting of blood or material that looks like coffee grounds

VALDECOXIB

Valdecoxib

phenyl-ethanone oxime

3-aryl-5-methylisoxazole

4-bromoisoxazole

arylboronic acids

Valdecoxib

• IUPAC Name:

• 4-(5-methyl-3-phenyl-1,2-oxazol-4-yl)benzenesulfonamide

• Drug name: BEXTRA

Valdecoxib

• Mechanism of Action• Valdecoxib is a nonsteroidal anti-inflammatory drug (NSAID) that exhibits anti-

inflammatory, analgesic and antipyretic properties. The mechanism of action is believed to be due to inhibition of prostaglandin synthesis primarily through inhibition of cyclooxygenase-2 (COX-2).

• At therapeutic plasma concentrations in humans valdecoxib does not inhibit cyclooxygenase-1 (COX-1).

• Absorption• Valdecoxib achieves maximal plasma concentrations in approximately 3 hours.

The absolute bioavailability of valdecoxib is 83% following oral administration of Valdecoxib compared to intravenous infusion of valdecoxib.

• Dose proportionality was demonstrated after single doses (1–400 mg) of valdecoxib.

• With multiple doses (up to 100 mg/day for 14 days), valdecoxib exposure as measured by the AUC, increases in a more than proportional manner at doses above 10 mg BID.

• Steady state plasma concentrations of valdecoxib are achieved by day 4.

Valdecoxib

• Distribution• Plasma protein binding for valdecoxib is about 98% over the concentration range (21–2384 ng/mL). • Steady state apparent volume of distribution (Vss/F) of valdecoxib is approximately 86 L after oral

administration.• Valdecoxib and its active metabolite preferentially partition into erythrocytes with a blood to

plasma concentration ratio of about 2.5:1. This ratio remains approximately constant with time and therapeutic blood concentrations.

• Metabolism• Valdecoxib undergoes extensive hepatic metabolism involving both P450 isoenzymes (3A4 and

2C9) and non-P450 dependent pathways (i.e., glucuronidation). Concomitant administration of Valdecoxib with known CYP 3A4 and 2C9 inhibitors (e.g., fluconazole and ketoconazole) can result in increased plasma exposure of Valdecoxib.

• One active metabolite of Valdecoxib has been identified in human plasma at approximately 10% the concentration of Valdecoxib. This metabolite, which is a less potent COX-2 specific inhibitor than the parent, also undergoes extensive metabolism and constitutes less than 2% of the valdecoxibdose excreted in the urine and feces. Due to its low concentration in the systemic circulation, it is not likely to contribute significantly to the efficacy profile of BEXTRA.

Valdecoxib

• Excretion• Valdecoxib is eliminated predominantly via hepatic metabolism with less

than 5% of the dose excreted unchanged in the urine and feces. About 70% of the dose is excreted in the urine as metabolites, and about 20% as valdecoxib N-glucuronide. The apparent oral clearance (CL/F) of Valdecoxib is about 6 L/hr. The mean elimination half-life (T1/2) ranges from 8–11 hours, and increases with age.

• Side effect:• Common side effects of Valdecoxib:• Acute Infection of the Nose, Throat or Sinus ,Diarrhea ,Feel Like Throwing

Up ,Head Pain ,Indigestion ,Stomach Cramps• Infrequent side effects of Valdecoxib:• Backache ,Dizzy ,Gas ,Muscle Pain ,Rash ,Sinus Irritation and Congestion

,Swelling of the Abdomen

PARECOXIB

Parecoxib

OCH

3

O O

CH3

N

O

CH3

SN

O OO

CH3

Na+

N

O

CH3

SNH

O OO

CH3

N

O

CH3

SNH

2

O O

(I)

(II)

TEA, DMAP

(III)

NaOH

Synthesis of Parecoxib sodium

+

valdecoxib

propionic anhydride

Parecoxib

Parecoxib

• IUPAC Name:

• N-[4-(5-methyl-3-phenyl-1,2-oxazol-4-yl)phenyl]sulfonylpropanamide

• Drug name: DYNASTAT

Parecoxib

• Absorption • Following IV or IM injection, Parecoxib sodium is rapidly and essentially completely converted to

Valdecoxib. • Exposure [plasma concentration vs. time under curve (AUC) and peak concentration (Cmax)] of

Valdecoxib following injection of parecoxib sodium is approximately linear.• Steady state was reached within 4 days.

• Distribution • The volume of distribution of valdecoxib after its IV administration is approximately 55 L.• Plasma protein binding is about 98% over the concentration range (0.21 – 2.38 mcg/mL) achieved

with the highest recommended dose. • is extensively partitioned into erythrocytes with an RBC to plasma concentration ratio of about 4:1

and a blood to plasma ratio of about 2.5:1. This ratio remains approximately constant with time and therapeutic blood concentrations, and therefore measurement of plasma concentrations of Valdecoxib in pharmacokinetics studies is appropriate.

Parecoxib

• Metabolism • Parecoxib is rapidly and almost completely converted to valdecoxib in vivo with a plasma half-life of <60

minutes. • The rate of conversion of Parecoxib to Valdecoxib is not affected in patients with mild to moderate hepatic

impairment. Elimination of Valdecoxib is by extensive hepatic metabolism involving multiple pathways. • The cytochrome P-450 (CYP-450) dependent pathway involves predominantly 3A4 and 2C9 isozymes while

the CYP-450 independent pathway leads to glucuronide conjugates of the sulfonamide moiety. • One active minor metabolite (a hydroxylated form via the CYP-450 pathway) of valdecoxib has been

identified in human plasma at approximately 10% the concentration of Valdecoxib.• sodium.

• Elimination • Following conversion from parecoxib, valdecoxib is eliminated via hepatic metabolism with <5% of the

dose excreted unchanged in the urine. No unchanged parecoxib is detected in urine and only a trace amount in faeces.

• The elimination half-life (T1/2) of Valdecoxib after IV or IM dosing of Parecoxib sodium is about 8 hours. • Plasma clearance (CLp) for Valdecoxib is about 6 L/hr. In patients undergoing haemodialysis the CLp of

Valdecoxib was similar to the CLp found in healthy subjects.

Parecoxib

• Side effect:

• Ulcer and gastrointestinal bleeding.• Jaundice and abnormal liver function.• Heart failure, heart attack, slow heart rate,

high/low blood pressure and abnormal heart rhythm.

• Swelling, rash, itching and difficulty in breathing.• Back pain, low platelet counts, agitation,

disturbed sleeping and decreased urination.

NON-SELECTIVE COX INHIBITOR

ASPIRIN

Aspirin

• Synthesis of Aspirin:

Salicylic acid acetic anhydride acetic acidAspirin

Aspirin

• IUPAC Name:

• 2-acetyloxybenzoic acid

• Drug name: ASPIRIN

Aspirin

• Mechanism of Action• The analgesic, antipyretic, and anti-inflammatory effects of aspirin are due to actions by both the

acetyl and the salicylate portions of the intact molecule as well as by the active salicylate metabolite.

• Aspirin directly and irreversibly inhibits the activity of both types of cyclo-oxygenase (COX-1 and COX-2) to decrease the formation of precursors of prostaglandins and thromboxanes from arachidonic acid

• . Salicylate may competitively inhibit prostaglandin formation. • Aspirin's antirheumatic (nonsteroidal anti-inflammatory) actions are a result of its analgesic and

anti-inflammatory mechanisms.• The platelet aggregation–inhibiting effect of aspirin specifically involves the compound's ability

to act as an acetyl donor to the platelet membrane.• Aspirin affects platelet function by inhibiting the enzyme prostaglandin cyclooxygenase in

platelets.• thereby preventing the formation of the aggregating agent thromboxane A2. This action is

irreversible; the effects persist for the life of the platelets exposed. • Aspirin may also inhibit formation of the platelet aggregation inhibitor prostacyclin (prostaglandin

I2) in blood vessels; however, this action is reversible.

Aspirin

• Absorption

• Absorption is generally rapid and complete following oral administration but may vary according to specific salicylate used, dosage form, and other factors such as tablet dissolution rate and gastric or intraluminal pH.

• Distribution

• Widely distributed to all tissues and fluids, including CNS, breast milk, and fetal tissues.

• Approximately 90% of salicylate is protein bound at concentrations of less than 100 mcg/mL and approximately 75% is bound at concentrations of more than 400 mcg/mL.

Aspirin

• Metabolism• As much as 80% of therapeutic doses of salicylate is metabolized in the liver.• This metabolism occurs primarily by hepatic conjugation with glycin to form

salicyluric acid or with glucuronic acid to form salicyl acyl and phenolic glucuronide, involving different metabolic pathways.

• Minor metabolites formed include gentisic acid, which appears to be the only active metabolite, but because of its small concentrations, it appears to play an insignificant role therapeutically.

• The predominant pathway is the conjugation with glycin, which is saturable. With low doses of aspirin approximately 90% of salicylate is metabolized through this pathway. As the maximum capacity of this major pathway is reached, the other pathways with a lower clearance become more important.

• Therefore, the half-life of salicylate depends on the major metabolic pathway used at a given concentration and becomes longer with increasing dosage.

Aspirin

• Elimination• Salicylates are excreted mainly by the kidneys as

salicyluric acid (75%). Urinary excretion of free salicylate accounts for 10% of the total elimination of salicylate.

• When small doses (less than 250 mg in an adult) are ingested, all pathways proceed by first-order kinetics, with an elimination half-life of about 2.0 to 4.5 hours.

• When higher doses of salicylate are ingested (more than 4 g), the half-life becomes much longer (15–30 hours). because the biotransformation pathways concerned with the formation of salicyluric acid and salicyl phenolic glucuronide become saturated.

Aspirin

• Side effect:• Common side effects of aspirin:

• Conditions of Excess Stomach Acid Secretion ,Feel Like Throwing Up,Heartburn ,Irritation of the Stomach or Intestines, Stomach Cramps, Throwing Up

• Rare side effects of aspirin:

• A Rupture in the Wall of the Stomach or Intestine ,Anemia ,Bleeding of the Stomach or Intestines ,Blood coming from Anus,Bronchospasm ,Decrease in the Ability of Platelet Cells to Clot,Decreased Blood Platelets ,Decreased White Blood Cells,Drowsiness ,Giant Hives ,Hemolytic Anemia ,Hemorrhage Within the Skull ,Hepatitis caused by Drugs ,Hives ,Inflammation of Skin caused by an Allergy ,Interstitial Nephritis ,Itching ,Large Purple or Brown Skin Blotches ,Life Threatening Allergic Reaction ,Reaction due to an Allergy ,Ringing in the Ears ,Seizures

ACETAMINOPHEN

Acetaminophen

• Synthesis of Acetaminophen:

phenol

4-aminophenol

4-nitrophenol

Acetaminophen

• IUPAC Name:

• N-(4-hydroxyphenyl)acetamide

• Drug name: TYLENOL

Acetaminophen

• Mechanism of action• Acetaminophen is thought to act primarily in the CNS, increasing the pain threshold by inhibiting

both isoforms of cyclooxygenase, COX-1, COX-2 enzymes involved in prostaglandin (PG) synthesis. Unlike NSAIDs, acetaminophen does not inhibit cyclooxygenase in peripheral tissues and, thus, has no peripheral anti-inflammatory affects.

• studies have found that acetaminophen indirectly blocks COX, and that this blockade is ineffective in the presence of peroxides. This might explain why acetaminophen is effective in the central nervous system and in endothelial cells but not in platelets and immune cells which have high levels of peroxides.

• Studies also report data suggesting that acetaminophen selectively blocks a variant of the COX enzyme that is different from the known variants COX-1 and COX-2. This enzyme is now referred to as COX-3. Its exact mechanism of action is still poorly understood, but future research may provide further insight into how it works.

• The antipyretic properties of acetaminophen are likely due to direct effects on the heat-regulating centres of the hypothalamus resulting in peripheral vasodilation, sweating and hence heat dissipation

• .

• Absorption:• The absorption of paracetamol by the oral route is rapid and complete. Maximum plasma

concentrations are reached 30 to 60 minutes following ingestion.

Acetaminophen

• Distribution:

• Acetaminophen is distributed rapidly throughout all tissues. Concentrations are comparable in blood saliva and plasma. Protein binding is low.

• Metabolism:

• Acetaminophen is metabolized mainly in the liver, following two major metabolic pathways:

1. Glucuronic acid and 2. sulfuric acid conjugates.• The latter route is rapidly saturated at doses higher than the therapeutic dosages. • A minor route, catalyzed by the Cytocrome P 450 (mostly CYP2E1), results in the

formation of an intermediate reagent (N-acetyl-p-benzoquinoneimine) which under normal conditions of use, is rapidly detoxified by glutathione and eliminated in the urine, after conjugation with cysteine and mercapturic acid.

Acetaminophen

• Elimination:• Elimination is essentially through the urine. 90% of the ingested

dose is eliminated via the kidneys within 24 hours, principally as glucuronide (60-80%) and sulphate conjugates (20-30%). Less than 5% is eliminated in unchanged form.

• Side effect• Get emergency medical help if you have any of these signs of an

allergic reaction to paracetamol: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Stop using this medication and call your doctor at once if you have a serious side effect such as:

• low fever with nausea, stomach pain, and loss of appetite;• dark urine, clay-colored stools; or• jaundice (yellowing of the skin or eyes).

KETROLAC

Ketorolac

• Mechanism of action:• Ketorolac is a nonsteroidal anti-inflammatory drug (NSAID) chemically related to

indomethacin and tolmetin. • Ketorolac tromethamine is a racemic mixture of [-]S- and [+]R-enantiomeric forms,

with the S-form having analgesic activity. Its anti-inflammatory effects are believed to be due to inhibition of both cylooxygenase-1 (COX-1) and cylooxygenase-2 (COX-2) which leads to the inhibition of prostaglandin synthesis leading to decreased formation of precursors of prostaglandins and thromboxanes from arachidonic acid.

• Analgesia is probably produced via a peripheral action in which blockade of pain impulse generation results from decreased prostaglandin activity. However, inhibition of the synthesis or actions of other substances that sensitize pain receptors to mechanical or chemical stimulation may also contribute to the analgesic effect.

• In terms of the ophthalmic applications of ketorolac - ocular administration of ketorolac reduces prostaglandin E2 levels in aqueous humor, secondary to inhibition of prostaglandin biosynthesis.

Ketorolac

• IUPAC Name:

• 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid

• Drug name: KETROLAC

Ketorolac

• Absorption• Ketorolac is 100% absorbed after oral administration . Oral administration• of Ketorolac after a high-fat meal resulted in decreased peak and delayed

time-to-peak concentrations of ketorolac tromethamine by about 1 hour.• Antacids did not affect theextent of absorption.

• Distribution• The mean apparent volume of ketorolac tromethamine following

complete distribution was approximately 13 liters. This parameter was determined from single dose data.

• The ketorolac tromethamine racemate has been shown to be highly protein bound (99%).

• Nevertheless, plasma concentrations as high as 10 mg/mL will only occupy• approximately 5% of the albumin binding sites. Thus, the unbound fraction

for each enantiomer will be constant over the therapeutic range.

Ketorolac

• Metabolism• Ketorolac tromethamine is largely metabolized in the liver. • The metabolic products are hydroxylated and conjugated forms of the parent drug. • The products of metabolism, and some unchanged drug, are excreted in the urine.

• Excretion• The principal route of elimination of ketorolac and its metabolites is renal. • About 92% of a given dose is found in the urine, approximately 40% as metabolites and 60% as• unchanged ketorolac. • Approximately 6% of a dose is excreted in the feces. A single-dose study with 10 mg Ketorolac

demonstrated that the S-enantiomer is cleared• approximately two times faster than the R-enantiomer and that the clearance was independent of

the route of administration.• This means that the ratio of S/R plasma concentrations decreases with time after each dose. • There is little or no inversion of the R- to S- form in humans. The clearance of the racemate in

normal subjects, elderly

Ketorolac

• Side effect:• Disturbances of the gut, such as diarrhea, constipation, indigestion,

nausea, vomiting or abdominal pain. Excess gas in the stomach and intestines (flatulence).Dry mouth. Loss of appetite. Ulceration or bleeding in the stomach or intestines (see warning section above).Inflammation of the stomach (gastritis) or pancreas (pancreatitis).Increased bleeding time for wounds. Drowsiness. Difficulty concentrating. Anxiety. Depression. Difficulty sleeping (insomnia). Hallucinations. Headache. Dizziness. Spinning sensation (vertigo). Visual disturbances. Shortness of breath. Skin reactions, such as itching, nettle rash. Excessive fluid retention in the body tissues, resulting in swelling (edema).High blood pressure (hypertension).Slow heartbeat or awareness of your heartbeat (palpitations). Flushing. Allergic reactions such as severe skin rashes, swelling of the lips, tongue and throat (angioedema) or narrowing of the airways (bronchospasm).Kidney, liver or blood disorders.

References1-CYCLOOXYGENASES 1 AND 2J. R. Vane,Y. S. Bakhle1, and R. M. Botting The William Harvey Research Institute, St Bartholomew’s and the Royal London School of Medicine and Dentistry, Queen Mary and Westfield College, Charterhouse Square, London EC1M 6BQ, United Kingdom

2-Synthesis of new rofecoxib analogs of expected anti-inflammatory activityKhaled R. A. Abdellatif1, Mohamed A. Abdelgawad1* and Nermeen A. Helmy

3- A general carbometalation, three component coupling strategyfor the synthesis of a,b-unsaturated c-sultines including thio-rofecoxib, a selective COX-2 inhibitor

David V. Smil,c Fabio E. S. Souzab and Alex G. Fallisa,*

4- Evolution of Nonsteroidal Anti-Inflammatory Drugs (NSAIDs):Cyclooxygenase (COX) Inhibition and Beyond

P. N. Praveen Rao1 and Edward E. Knaus2.

5- Metabolic Interactions in Rats Treated withAcetylsalicylic Acid and Trichloroethylene

B. Zielińska-Psuja, J. Orłowski, A. Plewka*, M. Kamiński*, J. Kowalówka-Zawieja, B. Zięba-Proc

6-Pharmacogenomicsofacetaminopheninpediatricpopulations:amovingtargetAnne E.Krasniak 1, GregoryT.Knipp2 , CraigK.Svensson1 and WanqingLiu 1*

7- http://en.wikipedia.org/wiki/Celecoxib8- http://en.wikipedia.org/wiki/Rofecoxib

References

9-http://quod.lib.umich.edu/m/medchem1ic/x-680/valdecoxib___tif

10- http://onlinelibrary.wiley.com/doi/10.1002/9781118541203.xen327/abstract

11- http://onlinelibrary.wiley.com/doi/10.1002/jhet.474/pdf

12- http://www.apexbt.com/valdecoxib.html

13- http://www.drugs.com/dosage/ibuprofen.html

14- http://my.clevelandclinic.org/health/drugs_devices_supplements/hic_COX-2_Nonsteroidal_Anti-inflammatory_Drugs_NSAIDs

15- http://www.drugs.com/drug-class/cox-2-inhibitors.html

16- http://en.wikipedia.org/wiki/Cyclooxygenase

17- http://osteoarthritis.about.com/od/osteoarthritismedications/a/cyclooxygenase.htm

18- http://www.merriam-webster.com/dictionary/cyclooxygenase

19- http://www.fasebj.org/content/12/12/1063.full

References

20- http://www.wisegeek.com/what-is-cyclooxygenase.htm21- http://emedicine.medscape.com/article/126919-overview22- http://pharmrev.aspetjournals.org/content/56/3/387.full23- http://medimoon.com/2013/05/difference-between-cox1-and-cox2/24- http://www.medicinenet.com/cox-2_inhibitors/page2.htm25- http://www.medicinenet.com/cox-2_inhibitors/page2.htm26- http://www.nature.com/nrd/journal/v3/n9/full/nrd1517.html27- http://www.oarsijournal.com/article/S1063-4584(05)00052-X/fulltext28- http://www.drugbank.ca/drugs/DB0048229- http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3813081/30- http://www.drugsbot.com/drugs/celecoxib/additional31- http://www.druglib.com/ratingsreviews/celebrex/32- https://www.pharmgkb.org/pathway/PA16581673633- http://www.drugs.com/celebrex.html34- http://www.rxlist.com/celebrex-side-effects-drug-center.htm35- http://www.druglib.com/activeingredient/rofecoxib/

References

36- http://www.druglib.com/reported-side-effects/vioxx/37- http://www.medicinenet.com/rofecoxib/page3.htm38- http://www.drugs.com/sfx/rofecoxib-side-effects.html39- http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3263766/40- http://www.druglib.com/druginfo/bextra/description_pharmacology/41- http://www.druglib.com/activeingredient/valdecoxib/42- http://www.ncbi.nlm.nih.gov/pubmed/1264247743- http://www.rxlist.com/bextra-drug/clinical-pharmacology.htm44- http://www.webmd.com/drugs/2/drug-22460/valdecoxib-oral/details/list-sideeffects45- http://en.wikipedia.org/wiki/Parecoxib46- http://www.chem24h.com/drug/synthesis/aioogjwwn.html47- http://www.druglib.com/trial/17/NCT00455117.html48- http://onlinelibrary.wiley.com/doi/10.1177/00912700122012607/abstract49- http://www.biomedcentral.com/1471-2253/3/150- https://www.wikigenes.org/e/chem/e/119828.html51- http://pubchem.ncbi.nlm.nih.gov/compound/aspirin#section=Top