Controversies over coxibs

Controversies over coxibs - Another cyclo-oxygenase isoform, so-called type 2 (COX-2) has been discovered in the early 1990s by Daniel Simmons and W. L. Xie,39 chemists at Brigham Young University in Provo, Utah. Simmons immediately understood the importance of his discovery. The same day the enzyme was sequenced, Provo, Utah. Simmons immediately understood the importance of his discovery. The same day the enzyme was sequenced,40 and he kept his notebook notarized as proof of his discovery. Subsequently, a new class of drugs, COX-2 inhibitors was developed after researchers at the University of Rochester discovered the gene in humans that is responsible for producing the COX-2 and revealed the enzyme’s role in causing infl ammation within individual cells. 

The team, lead by Donald Young (University of Rochester Medical Centre), provided the basic understanding of the role of COX-2 in disease showing that selectively blocking the activity of the enzyme would be benefi cial in treating his discovery. Subsequently, a new class of drugs, COX-2 inhibitors was developed after researchers at the University of Rochester discovered the gene in humans that is responsible for producing the COX-2 and revealed the enzyme’s role in causing infl ammation within individual cells. 

The team, lead by Donald Young (University of Rochester Medical Centre), provided the basic understanding of the role of COX-2 in disease showing that selectively blocking the activity of the enzyme would be benefi cial in treating II. Two Hundred Years of Drug Discoveries infl ammation.41 Besides the constitutive COX-1, participating to stomach protection and renal artery vasodilatation, this COX-2 enzyme, induced by infl ammatory phenomena and cytokines stimulation, allowed to design specifi c inhibitors,“ coxibs, ” playing an increasing but controversial role in the struggle against infl ammation. This discovery set in motion a worldwide race among pharmaceutical companies to identify drugs that would restrain the action of the enzyme and, in turn, reduce infl ammation and pain. There may be other forms of COX that could account for some of the remaining discrepancies in action amongst non-steroidal anti-infl ammatory drugs (NSAIDs). this COX-2 enzyme, induced by infl ammatory phenomena and cytokines stimulation, allowed to design specifi c inhibitors,“ coxibs, ” playing an increasing but controversial role in the struggle against infl ammation. This discovery set in motion a worldwide race among pharmaceutical companies to identify drugs that would restrain the action of the enzyme and, in turn, reduce infl ammation and pain. There may be other forms of COX that could account for some of the remaining discrepancies in action amongst non-steroidal anti-infl ammatory drugs (NSAIDs).42 COX-2 inhibitors were apparently safer from a digestive point of view but questionable for their cardiovascular effects. Selective inhibitors of COX-2 cause less endoscopically visualized gastric ulceration in arthritis patients than equi-effi cacious doses of traditional NSAIDs, which coincidentally inhibit COX-1 and COX-2. COX-2 inhibitors suppress substantially platelet inhibitory, vasodilator prostaglandins, such as prostacyclin (PGI but questionable for their cardiovascular effects. Selective inhibitors of COX-2 cause less endoscopically visualized gastric ulceration in arthritis patients than equi-effi cacious doses of traditional NSAIDs, which coincidentally inhibit COX-1 and COX-2. COX-2 inhibitors suppress substantially platelet inhibitory, vasodilator prostaglandins, such as prostacyclin (PGI2 ), without coincidental inhibition of the platelet agonist vasoconstrictor thromboxane (TxA the platelet agonist vasoconstrictor thromboxane (TxA2 ). 

As PGI As PGI2 counters the cardiovascular effects of TxA2 and augments the response to thrombotic stimuli augments the response to thrombotic stimuliin vivo , this affords a plausible mechanism by which COX-2 inhibitors might enhance the risk of thrombosis in otherwise predisposed individuals. After being marketed in 1999 rofecoxib (Vioxx®) has been withdrawn in 2004, because of an excess risk of myocardial infarctions and strokes. Despite the withdrawal, controversies remain. Although the nonselective NSAIDs can cause life-threatening gastric toxicity, the risk for any single patient is fairly low when COX-2 inhibitors are compared with two non-selective NSAIDs. affords a plausible mechanism by which COX-2 inhibitors might enhance the risk of thrombosis in otherwise predisposed individuals. After being marketed in 1999 rofecoxib (Vioxx®) has been withdrawn in 2004, because of an excess risk of myocardial infarctions and strokes. Despite the withdrawal, controversies remain. Although the nonselective NSAIDs can cause life-threatening gastric toxicity, the risk for any single patient is fairly low when COX-2 inhibitors are compared with two non-selective NSAIDs.43

Among those controversies, the question whether selective COX-2 inhibitors are prothrombotic, or not, is not theoretical. Whereas aspirin and traditional NSAIDs inhibit both thromboxane A 2 and prostaglandin I2 , the coxibs leave thromboxane A thromboxane A 2 generation unaffected, refl ecting the absence of COX-2 in platelets. Thus, this single mechanism might be expected to elevate blood pressure, accelerate atherogenesis, and predispose patients receiving coxibs to an exaggerated thrombotic response to the rupture of an atherosclerotic plaque. absence of COX-2 in platelets. Thus, this single mechanism might be expected to elevate blood pressure, accelerate atherogenesis, and predispose patients receiving coxibs to an exaggerated thrombotic response to the rupture of an atherosclerotic plaque.44 Clinical observations and studies found that taking common NSAIDs was linked to a lower risk of certain cancers. 

When celecoxib was approved for familial adenomatous polyposis in 1999, there was hope that other COX-2 inhibitors would also prove to be safe and powerful anticancer treatments. This is not the case. Structural differences between celecoxib and rofecoxib could explain this discrepancy. A systematic chemical approach allowed to produce 50 compounds tested for their ability to induce apoptosis in human prostate cancer cells, confi rmed that the structural requirements for the induction of apoptosis are distinct from those that mediate COX-2 inhibition.

Apoptosis induction requires a bulky terminal ring, a heterocyclic system with negative electrostatic potential and a benzenesulfonamide or benzenecarbonamide moiety. Ching Shih Chen found that taking common NSAIDs was linked to a lower risk of certain cancers. When celecoxib was approved for  familial adenomatous polyposis in 1999, there was hope that other COX-2 inhibitors would also prove to be safe and powerful anticancer treatments. This is not the case. Structural differences between celecoxib and rofecoxib could explain this discrepancy. A systematic chemical approach allowed to produce 50 compounds tested for their ability to induce apoptosis in human prostate cancer cells, confi rmed that the structural requirements for the induction of apoptosis are distinct from those that mediate COX-2 inhibition. 

Apoptosis induction requires a bulky terminal ring, a heterocyclic system with negative electrostatic potential and a benzenesulfonamide or benzenecarbonamide moiety. Ching Shih Chenet al. (Columbus, USA) modifi ed the structure of rofecoxib to create compounds that mimicked the surface electrostatic potential of celecoxib, one of which showed a substantial increase in apoptotic activity. of rofecoxib to create compounds that mimicked the surface electrostatic potential of celecoxib, one of which showeda substantial increase in apoptotic activity.45 What a challenge for the future!