Update on COX-2 inhibitor patents with a focus on optimised formulation and therapeutic scope of drug combinations making use of COX-2 inhibitors

Abstract

Selective cyclooxygenase-2 (COX-2) inhibitors, like coxibs, demonstrate efficacy in the treatment of pain and inflammation, comparable to unselective non-steroidal anti-inflammatory drugs (NSAIDs). COX-2 expression was, for a long time, linked only to pathophysiology, but ongoing research has also demonstrated constitutive COX-2 expression within normal tissues such as brain, kidney, pancreas, intestine and blood vessels. Irrespective of their tendency to reduce severe gastrointestinal (GI) events, strong debates have been ignited regarding new adverse effects of specific COX-2 inhibitors, most notably those of a cardiovascular (CV) nature, such as blood pressure elevation, myocardial infarction and stroke. This review evaluates the recent patent literature concerning new therapeutic options offered by selective COX-2 inhibitors, with emphasis on technological improvements and COX-2 inhibitors as components of drug combinations

Macrophages: An elusive yet emerging therapeutic target of atherosclerosis

“…[322][323][324] TXA2 actions are mediated through its TP receptor. 322,[325][326][327] The COX-1 inhibitors, like aspirin, have the advantage of inhibiting TXA2 production, but under such conditions production of other TP receptor ligands, such as hydroxyeicosatetraenoic acids 328 and F 2 -IPs 329 that are formed by endothelial cells, circulating monocytes and macrophages in the atherosclerotic plaque in response to oxidative stress, remains unaltered and hence the strategy may not be fully effective.…”

Pathogenic Mechanisms andIn VitroDiagnosis of AERD

“…The pharmacological hallmark of acetylsalicylic acid and other NSAIDs is the blocking of COX-enzymes causing reduction and/or loss of prostaglandin (PG) production as demonstrated in 1971 by Ferreira and colleagues [ 14 ], Smith and Willis [ 15 ], and Vane [ 16 ]. Meanwhile there are several other NSAIDs known to inhibit the three known COX-isoenzymes, depending on their selectivity (an overview is given in Table 2 , for review see [ 17 ]).…”

“…Its clinical relevance to COX-3 remains unproven. All COX isoenzymes are modified by NSAIDs with different efficacy (for review see [ 17 , 27 , 29 ]). The resulting metabolite PGH 2 is further metabolised by PGE-synthase forming PGE 2 .…”

Update on COX-2 Selective Inhibitors: Chemical Classification, Side Effects and their Use in Cancers and Neuronal Diseases

“…34). Cyclooxygenase Inhibitor-Nitric Oxide Donors (CINODS) [155] were synthesized by modifying coxibs with introduction of a NO-donor group and displayed a reduced cardiovascular risk compared to selective COX-2 compounds [156][157][158][159][160][161][162][163][164]. Since NO and H 2 S act in concert for the maintenance of gastric mucosa, dual H 2 S-NO releasing compounds were also elaborated [156,165] (compounds 372 g-j, see Table 99) (Fig.…”

“…These side effects are the consequence of an over aggregation of platelets, obstructing arterials and vessels, [179] and can result in myocardial infarction, atherosclerosis, chronic heart failure and hypertension [177,[180][181][182][183]. They led to the withdrawal from the market of several coxibs, notably rofecoxib in 2004 and valdecoxib in 2005 [155,184]. The CV adverse effects were first associated with the disequilibrium of the balance between the COX-1 TXA2 prothrombotic effects and the COX-2 PGI2 antithrombotic effects [177,179,184].…”