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Abstract
Cyclooxygenase enzymes were classified into: Cyclooxygenase-1 (COX-1) and Cyclooxygenase –2(COX-2) which catalyse the rate limiting steps of prostaglandin synthesis and are the target of NSAIDs Dan Simmon’s group report the discovery of a novel cyclooxygenase (COX-1) enzyme variant that could be the target of acetaminophen and other analgesic / antipyretic drugs which they have named COX-3, as well as two smaller COX-1-derived proteins (partial COX1) PCOX1a and PCOX1b. The COX3, but not PCOX1a, possesses glycosylation-dependent cyclooxygenase activity.
The discovery of this new COX-3 expalin new aspect of mechanism of action of paracetamol, the most widely used analgesic drug in the world. The authors postulated that inhibition of COX-3 could represent a primary central mechanism by which these drugs decrease pain and possibly fever.
The clinical ramifications and knowledge of COX isozymes are rapidly expanding and may offer significant hope for future treatments of pain, inflammation, and fever.
Two experimental methods were applied in this work :
I.Methods for assessing analgesia
II.Methods for assessing inflammation.
I.Methods for assessing analgesia
Four types of antinociceptive assays were employed in this study, which are: (1) Hot plate test, (2) Formalin test, (3) Mechanical noxious stimulus (Paw pressure) and (4) Writhing test.
Assesment of analgesia was performed on 42 adult animals for each procedure. Animals were randomly divided into 5 groups according to the treatment received:
Group (1) : Control group (No =6)
Animals were given distilled water 0.1ml/100gm BW orally.
Group (2) : Paracetamol treated group (No =18) animals treated with paracetamol in doses of (66.2, 132.4, and 264.4µmol/kg).
Group (3) : Acetylsalicylic acid treated group (No =6) animals received a single oral dose of (138.8µmol/kg).
Group (4) : Ketoprofen treated group (No =6) animals received a single oral dose of (204µmol/kg).
Group (5) :Celecoxib treated group (No =6) animals treated with celecoxcib in dose of (105µmol/kg).
The results observed in the present study showed that, paracetamol at doses of 66.2, 132.4, and 264.4µmol/kg orally produced dose dependent antinociceptive effect in all models used.
In hot plate test, results also showed that 132.4 µmol/kg. paracetamol is about equipotent to Aspirin (138.8µmol/kg), and the ketoprofen (204µmol/kg) is the most potent one .
In formalin test, it was observed that all drugs used significantly reduced the total number of flinching during phase-1 and phase-2. The % inhibition was more effective and potent in the group of animals treated with ketoprofen especially during phase-IIA and B. paracetamol (264.4µmol/kg) was about equipotent to ketoprofen during phase II
In Paw pressure test, the results demonstrated that the increase of nociceptive threshold was more effective and potent in the group of animals treated with ketoprofen. Also, it was observed that 132.4µmol/kg paracetamol is about equipotent to Aspirin (138.8µmol/kg).
And in the forth test (Writhing test),It was observed that the decrease of no. of writhing was more effective and potent in the group of animals treated with ketoprofen , Also, it was observed that 132.4µmol/kg paracetamol is about equipotent to celecoxcib.
II.Methods for assessing inflammation
In this study two models of inflammation were used: (1) Dextran-induced edema (Acute model), and formaldehyde induced arthritis (chronic model).
In dextran-induced edema, results revealed that, Prior administration of paracetamol (132.4µmol/kg) or Aspirin (138.8µmol/kg), ketoprofen (204µmol/kg), and celecoxcib (105µmol/kg) significantly attenuated the increase in paw volume; the maximum effect was observed after 3hours.
In chronic method, an oral pretreatment with paracetamol (132.4, and 264.4µmol/kg), Aspirin (138.8µmol/kg), Ketoprofen (204µmol/kg), and celecoxcib (105µmol/kg) produced a significantly inhibitory effect on developing arthritis from day (3) to day (11) of experiment.
The higher inhibitory effect was observed at day (5). At this time paracetamol (264.4µmol/kg) was about equipotent to ketoprofen.
The results of this method were supported with histopathological examination.
The role of NO and ATP. Sensitive K channel pathways in antinociceptive effect of paracetamol was investigated: Pretreatment of rats with L-NAME an inhibitor of NO synthase (10mg/kg I.P) 15 min. prior to oral administration of paracetamol (132.4µmol/kg) reversed the antinociceptive effect of paracetamol In contrast, Glibenclamide (80µg/kg) which is a ATP-sensitive K channel blocker failed to modify the antinociceptive effect of paracetamol to mechanical stimuli.
Lastely, paracetamol in concentration of 50, 100, and 200µg significantly reduce both HR. and CF. in isolated perfused rat heart.
Conclusion
The data elicited in the present work demonstrated that, paracetamol possessed peripheral as well as central antinociceptive activity. The mechanism(s) was complex and both COX- inhibition and NO synthase pathways were involved. Contribution of COX-3 was suggested.
The data of anti-inflammatory assessment provides evidence that paracetamol has anti-inflammatory activity comparable to ketoprofen especially in formaldehyde-induced arthritis. Data suggested possible involvement of COX-3 isoenzyme.