A Comparative study of SC-560, celecoxib and paracetamol in fever, pain and inflammation in rodents.

Abstract

Cyclooxygenase (COX) is a key enzyme in prostaglandin synthesis and the target for nonsteroidal anti-inflammatory drugs. Three COX enzymes are involved in prostaglandin synthesis, COX-1, COX-2 and a recently discovered splice-variant of COX-1, COX-3. The present study was carried out to evaluate and compare the anti-nociceptive, antipyretic and anti-inflammatory effects of SC-560, celecoxib and paracetamol which are selective inhibitors of COX-1, COX-2 and COX-3 respectively, based on in-vivo pharmacological assays. Methods: Animals were divided randomly into different groups: control, SC-560, celecoxib, paracetamol, paracetamol + SC-560, paracetamol + celecoxib and SC-560 + celecoxib. The hot-plate and acetic acid-induced writhing tests was used to evaluate the anti-nociceptive activity, yeast-induced hyperpyrexia test was used to evaluate the antipyretic activity while, carrageenan-induced paw edema test utilized to access as for antiinflammatory activity. PGE2, IL-6 and RANTES (the study markers) were measured by ELISA biochemical technique in order to support the results and to show the effects of different COX inhibitors. Results: Celecoxib and paracetamol exhibited significant anti-nociceptive effect (p <0.01 and p <0.001, respectively) when assessed using the hot-plate and acetic acid-induced writhing tests, while SC-560 exhibited significant anti-nociceptive effect (p <0.01) only in acetic acid-induced writhing test. Paracetamol plus celecoxib (p <0.001) was the only combination that caused significant anti-nociceptive effect on both models as compared to each drugs alone. The anti-nociceptive order of potency was paracetamol≥ celecoxib> SC-560. Celecoxib and paracetamol -but not SC-560- produced significant (p <0.01) antipyretic effect when assessed using the brewer’s yeast-induced pyrexia test. Coadministration of paracetamol plus celecoxib caused a significance increased of antipyretic effect as compared to each drug alone. The relative order of potency was celecoxib> paracetamol> SC-560. Likewise, celecoxib and paracetamol exhibited significant antiinflammatory effect (p <0.01 and p <0.05, respectively) when assessed using the carrageenan-induced paw edema test. Interestingly celecoxib reduced both serum and brain levels of the PGE2, IL-6 and RANTES, while paracetamol reduced their levels only in the brain. SC-560 reduced only the serum levels of the markers. Conclusion: These in vitro and in vivo results provide a clear idea about the role of COX1, COX-2 and COX-3 enzymes inhibition in nociception, hyperthermia and inflammation. It appears that COX-2 and COX-3 enzymes are involved in the nociceptive and hyperthermic pathways; inhibition of these two enzymes by celecoxib and paracetamol respectively, explains their usefulness in the treatment of pain and hyperthermia. Furthermore, COX-2 enzyme plays a significant role in the inflammatory pathway thus, when it is inhibited, inflammation is reduced. On the other hand, SC-560 the selective COX-1 enzyme inhibitor, at therapeutic doses, did not play a significant role in pain, fever nor inflammation.