presentation discover selective and non selective cox inhibitor

1. Pharmacophore of COX-inhibitor
Under supervision:
Dr.Mohammed Taha

2. 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

3. Cyclooxygenase (COX)
• Known as : prostaglandin-endoperoxide
synthase (PTGS).
• that is responsible for formation of
prostanoids:
1. Prostaglandins
2. Prostacyclin
3. Thromboxane.
• involved in the inflammatory response.

4. Cyclooxygenase (COX)
• Contains two separate active sites for
prostaglandin synthase
1. One side contains the cyclooxygenase active
site
2. The opposite side contains the peroxidase
active site which is involved in activating the
heme group necessary for cyclooxygenase
reaction
• Has two forms, COX1 and COX2.

5. 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

6. 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

8. COX:

9. Selective cox-2 inhibitor

10. CELECOXIB

11. Celecoxib
Synthesis 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.

12. Celecoxib
• IUPAC Name:
4-[5-(4-methylphenyl)-3(trifluoromethyl)pyrazol-
1-yl]benzenesulfonamide
• Drug name: CELEBREX

13. 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.

14. 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.

15. 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.

16. ROFECOXIB

17. Rofecoxib
• Synthesis of Rofecoxib:
phenylacetic acid
butenolide
triflate4-bromothioanisole
organoboric acid

18. Rofecoxib
• IUPAC Name:
• 3-(4-methylsulfonylphenyl)-4-phenyl-2H-
furan-5-one
• Drug name: VIOXX

19. 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.

20. 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-mg
dose 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 rifampin
600 mg daily produces a 50% decrease in rofecoxib plasma
concentrations.

21. 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

22. VALDECOXIB

23. Valdecoxib
phenyl-ethanone oxime
3-aryl-5-methylisoxazole
4-bromoisoxazole
arylboronic acids

24. Valdecoxib
• IUPAC Name:
• 4-(5-methyl-3-phenyl-1,2-oxazol-4-
yl)benzenesulfonamide
• Drug name: BEXTRA

25. 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.

26. 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 valdecoxib
dose 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.

27. 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

28. PARECOXIB

29. Parecoxib
O
CH3
O O
CH3
N
O
CH3
S
N
O O
O
CH3
Na
+
N
O
CH3
S
N
H
O O
O
CH3
N
O
CH3
S
NH2
O O
(I)
(II)
TEA, DMAP
(III)
NaOH
Synthesis of Parecoxib sodium
+
valdecoxib
propionic anhydride
Parecoxib

30. Parecoxib
• IUPAC Name:
• N-[4-(5-methyl-3-phenyl-1,2-oxazol-4-
yl)phenyl]sulfonylpropanamide
• Drug name: DYNASTAT

31. 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.

32. 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.

33. 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.

34. NON-SELECTIVE COX INHIBITOR

35. ASPIRIN

36. Aspirin
• Synthesis of Aspirin:
Salicylic acid acetic anhydride acetic acidAspirin

37. Aspirin
• IUPAC Name:
• 2-acetyloxybenzoic acid
• Drug name: ASPIRIN

38. 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.

39. 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.

40. 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.

41. 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.

42. 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

43. ACETAMINOPHEN

44. Acetaminophen
• Synthesis of Acetaminophen:
phenol
4-aminophenol
4-nitrophenol

45. Acetaminophen
• IUPAC Name:
• N-(4-hydroxyphenyl)acetamide
• Drug name: TYLENOL

46. 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.

47. 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.

48. 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).

49. KETROLAC

50. 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.

51. Ketorolac
• IUPAC Name:
• 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-
carboxylic acid
• Drug name: KETROLAC

52. 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.

53. 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

54. 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.

55. References
1-CYCLOOXYGENASES 1 AND 2
J. 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 activity
Khaled 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/Celecoxib
8- http://en.wikipedia.org/wiki/Rofecoxib

56. 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

57. References
20- http://www.wisegeek.com/what-is-cyclooxygenase.htm
21- http://emedicine.medscape.com/article/126919-overview
22- http://pharmrev.aspetjournals.org/content/56/3/387.full
23- http://medimoon.com/2013/05/difference-between-cox1-and-cox2/
24- http://www.medicinenet.com/cox-2_inhibitors/page2.htm
25- http://www.medicinenet.com/cox-2_inhibitors/page2.htm
26- http://www.nature.com/nrd/journal/v3/n9/full/nrd1517.html
27- http://www.oarsijournal.com/article/S1063-4584(05)00052-X/fulltext
28- http://www.drugbank.ca/drugs/DB00482
29- http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3813081/
30- http://www.drugsbot.com/drugs/celecoxib/additional
31- http://www.druglib.com/ratingsreviews/celebrex/
32- https://www.pharmgkb.org/pathway/PA165816736
33- http://www.drugs.com/celebrex.html
34- http://www.rxlist.com/celebrex-side-effects-drug-center.htm
35- http://www.druglib.com/activeingredient/rofecoxib/

58. References
36- http://www.druglib.com/reported-side-effects/vioxx/
37- http://www.medicinenet.com/rofecoxib/page3.htm
38- http://www.drugs.com/sfx/rofecoxib-side-effects.html
39- 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/12642477
43- http://www.rxlist.com/bextra-drug/clinical-pharmacology.htm
44- http://www.webmd.com/drugs/2/drug-22460/valdecoxib-oral/details/list-sideeffects
45- http://en.wikipedia.org/wiki/Parecoxib
46- http://www.chem24h.com/drug/synthesis/aioogjwwn.html
47- http://www.druglib.com/trial/17/NCT00455117.html
48- http://onlinelibrary.wiley.com/doi/10.1177/00912700122012607/abstract
49- http://www.biomedcentral.com/1471-2253/3/1
50- https://www.wikigenes.org/e/chem/e/119828.html
51- http://pubchem.ncbi.nlm.nih.gov/compound/aspirin#section=Top