Nonsteroid antiphlogistic drugs as aspirin, ibuprofen and nurofen are widely used in the medicine. All drugs from this group are inhibitors of cyclooxygenase which is indicated COX as well. Cyclooxygenase products prostaglandin-H2 which is precursor of others bioactive prostaglandins, several from them (for instance, prostaglandin-E2) are mediators of inflammations. As many others drugs, antiphlogistic medications influence the organism badly. Thus, during the long treatment by high doses of aspirin the blood coagulability decreases defense mechanisms in the cells of mucous coat of stomach damage that increases the risk of stomach ulcer.

Two enzyme isoforms were discovered - COX-1 and COX-2, and mechanisms of their regulation of expression significantly differ. COX-1 was referred as constitutive, because it presents in the majority of cells, independently of the external action. On the contrary, COX-2 is inducible form, expression of which activates in some cells after external action. Thus, stimulation by interleukin during the inflammatory response in the endothelial cells results in COX-2 production.

A number of medications (celecoksib, rofecoksib) which selectively inhibit COX-2 have been recently developed. These drugs slightly change prostaglandins balance in the “healthy” tissues, but suppress prostaglandins production in the inflammatory foci, that allow decreasing the risk of stomach ulcer for the patients, taking antiphlogistic drugs protractedly. However clinical trials reveal that using of “coksibs” may cause increase of thrombotic risk (infarction and stroke)

It connected with the fact that selective inhibition of COX-2 in the endothelial cells decreases prostacyclin production which has antimicrobial effect. At the same time in the trombicytes, containing COX-1 only, remains the rate of production of other prostaglandin-H2 derivative – tromboxan, which promotes trombus formation.

The aim of our project is to analyze the action of various types inhibitors of COX on the basis of kinetic modeling of processes of prostaglandins biosynthesis in the system endothelium–plasma–trombocytes. Revelation of processes which are most responsible for thrombotic risk decreasing will help to develop effective antiflogistic medicals and/or optimize the regimen of taking of existing medicals.

Following directions were chosen in the projects:

1. Detailed scheme of cyclooxygenase (COX) catalytic cycle development. Testing of catalytic scheme COX in the reductive “flowing” kinetic model of prostaglandin-H2 synthesis from arachidonic acid. Modelling of process of COX inhibition by several types of antiflogistic drugs.
2. Detailed kinetic model of trombocyt development, which includes subsystems of intracellular signaling, prostaglandin biosynthesis, prostaglandin transport between cell and environment. Trombocyts are leading participants in the process of thrombus formation: on their surface locate receptors to both prostacyclin (inhibits thrombus formation) and thromboxane (stimulates thrombus formation).
3. Model of the system endothelium–plasma–trombocytes development. This model reflects prostaglandins production in the various types of cells and their transport between cells through the plasma. Finally, exactly the ratio of different prostaglandins concentrations in the blood plasma is the characteristic of presence or absence of thrombotic risk.

Publications

More detail information about this project you could find in the artycle - Goltsov A., Maryashkin A., Swat M., Kosinsky Y., Humphery-Smith I., DeminO., Goryanin I., Lebedeva G. Kinetic modelling of NSAID action on COX-1: focus on in vitro/in vivo aspects and drug combinations (2009) Europ J Pharmac Sciences. 36(1), 122–136.