Recent Development in the Field of Dual COX / 5-LOX Inhibitors

Julémont, Fabien; Dogné, Jean‐Michel; Pirotte, Bernard; Leval, Xavier de

doi:10.2174/1389557043403747

Cited by 27 publications

(24 citation statements)

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“…In contrast, the nonselective COX-1/COX-2 inhibitor piroxicam decreased prostaglandin production from canine mast cells, but the production of leukotrienes appeared to increase following treatment. This is consistent with previous data suggesting that inhibition of COX pathways may induce an upregulation of 5-LOX based leukotrienes (Julemont et al, 2004; Mao et al, 2004). In contrast, NDGA, a selective 5-LOX inhibitor induced the opposite effect on canine mast cells, decreasing leukotriene production while increasing prostaglandin production.…”

Section: Discussionsupporting

confidence: 93%

“…Previous studies evaluating inhibition of 5-LOX by Zileuton® demonstrated enhanced thromboxane A2 production and increased platelet aggregation (Wu et al, 2003), implying a similar “shunting” of lipid mediators to the COX pathway after 5-LOX inhibition. Given the potential paradoxical effects of COX-only or LOX-only inhibition, dual inhibitors of COX and LOX have been suggested to be potentially more useful for the clinical management of inflammatory conditions without gastrointestinal toxicity (Julemont et al, 2004). …”

Section: Discussionmentioning

confidence: 99%

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Characterization and modulation of canine mast cell derived eicosanoids

Lin

London

2010

Veterinary Immunology and Immunopathology

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Mast cells play an important role in both innate and acquired immunity as well as several pathological conditions including allergy, arthritis and neoplasia. They influence these processes by producing a variety of mediators including cytokines, chemokines and eicosanoids. Very little is currently known about the spectrum of inflammatory mediators, particularly eicosanoids (prostaglandins and leukotrienes), produced by canine mast cells. This is important since modulating mast cell derived eicosanoids may help in the treatment of autoimmune and inflammatory disorders. The purpose of this study was to investigate the spectrum of eicosanoids produced by normal canine mast cells and to evaluate the effects of cytokines and non-steroidal anti-inflammatory mediators (NSAIDS) on eicosanoid production and release. Canine bone marrow derived cultured mast cells (cBMCMCs) expressed COX-1, COX-2, and 5-LOX and synthesized and released PGD2, PGE2, LTB4, and LTC4 following activation by a variety of stimuli. The selective COX-2 NSAIDs carprofen (Rimadyl®) and deracoxib (Deramaxx®) inhibited PGD2 and PGE2 production but only slightly inhibited LTB4 and LTC4. The mixed COX-1/COX-2 inhibitor piroxicam blocked PGD2 and PGE2 production, but upregulated LTC4 following treatment while tepoxilan (Zubrin®), a pan COX/LOX inhibitor, markedly reduced the production of all eicosanoids. The LOX inhibitor nordihydroguaiaretic acid (NDGA) prevented LTB4/LTC4 release and BMBMC degranulation. Pre-incubation of cBMCMCs with IL-4 and SCF sensitized these cells to degranulation in response to substance P. In conclusion, canine BMCMCs produce an array of eicosanoids similar to those produced by mast cells from other species. Tepoxilan appeared to be the most effective NSAID for blocking eicosanoid production and thus may be useful for modulating mast cell mediated responses in dogs.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Characterization and modulation of canine mast cell derived eicosanoids

Lin

London

2010

Veterinary Immunology and Immunopathology

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“…[72][73][74][75][76][77][78]; 3) thiophene derivatives (RWJ-63556) [79,80]; 4) pyrazoline derivatives (phenidone, BW-755C) [81]; 5) pyrrolizine derivatives (licofelone, etc.) [82][83][84][85].…”

Section: Drugs Able To Inhibit Both Cyclooxy-genases (Cox-1 And/or Comentioning

confidence: 99%

Dual Acting Anti-Inflammatory Drugs

Leone¹,

Ottani²,

Bertolini

2007

CTMC

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Drugs able to inhibit both cyclooxygenases (COX-1 and COX-2) and 5-lipoxygenase (5-LOX) (dual acting anti-inflammatory drugs) have been designed in order to obtain compounds that retain the activity of classical nonsteroidal anti-inflammatory drugs (NSAIDs) while avoiding their main drawbacks. The classical NSAIDs display their anti-inflammatory action mainly through inhibition of COX and one of their main drawbacks is the curtailed production of gastroprotective prostaglandins (PGs) being associated with the concurrent increased production of the gastro-damaging and bronchoconstrictive leukotrienes (LTs). Leukotrienes and cysteinyl-leukotrienes are moreover pro-inflammatory and increase microvascular permeability. One of the leukotrienes (LTB(4)) is the most potent chemotactic agent and it induces chemotaxis of eosinophils, neutrophils and monocytes in the inflamed tissue, increases superoxide generation and proinflammatory cytokines production. It is further advantageous for a drug to have both COX and 5-LOX inhibiting activities because prostaglandins enhance leukotriene-mediated inflammation. Various structural families of dual inhibitors have been designed and several compounds are currently undergoing clinical development. In the post-COX-2 selective inhibitors era, these dual acting inhibitors may turn out to be promising new drugs to treat inflammatory diseases and possibly other diseases. Indeed, both COX-2 and 5-LOX are also involved in the development and progression of several types of cancer; in these conditions, selective inhibition of COX-2 alone may lead to a shunt of arachidonic acid metabolism towards the leukotriene pathway, and therefore the blockade of both COX-2 and 5-LOX may produce a better anticancer response. In addition, the dual inhibition of both COX and 5-LOX is neuroprotective by suppressing toxic actions of reactive microglia and macrophages, that are increased in aging brain and in age-related degenerative conditions, particularly Alzheimer's and Parkinson's diseases. Finally, the blockade of 5-LOX does not impair the synthesis of lipoxins (LXs), which are mainly produced by further lipoxygenation of 15-HPETE, and which have potent anti-inflammatory properties and can be considered as stop-signal mediators. Leukocyte 15-LOX and platelet 12-LOX by intercellular mechanism via leukocyte/platelet cell-cell interaction convert 15-HPETE into lipoxins.

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“…A number of studies have demonstrated that leukotrienes are important regulators of cancer cell proliferation and cause apoptosis in non-cancer cells [41], [42], [43], [44], [45] and [46]. Since, AA is metabolized via LOX-5 into leukotrienes, specific inhibition of LOX-5 may shunt the AA metabolism by LOX-5 leading to the decreased formation of leukotrienes.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of aldose reductase prevents endotoxin-induced inflammation by regulating the arachidonic acid pathway in murine macrophages

Mohammed

Yadav

Srivastava

et al. 2011

Free Radical Biology and Medicine

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Bacterial endotoxin, lipopolysaccharide (LPS) is known to induce release of arachidonic acid (AA) and its metabolic products which play important role in inflammatory process. We have shown earlier that LPS-induced signals in macrophages are mediated by aldose reductase (AR). Here we have investigated the role of AR in LPS-induced release of AA metabolites and their modulation using a potent pharmacological inhibitor fidarestat and AR-siRNA ablation in RAW 264.7 macrophages, and AR-knockout mice peritoneal macrophages and heart tissue. Inhibition or genetic ablation of AR prevented the LPS-induced synthesis and release of AA metabolites such as PGE2, TXB, PGI2 and LTBs in macrophages. LPS-induced activation of cPLA2 was also prevented by AR inhibition. Similarly, AR inhibition also prevented the calcium ionophore A23187 –induced cPLA2 and LTB4 in macrophages. Further, AR inhibition with fidarestat prevented the expression of AA metabolizing enzymes such as COX-2 and LOX-5 in RAW 264.7 cells and AR-knockout mice derived peritoneal macrophages. LPS-induced expression of AA metabolizing enzymes and their catalyzed metabolic products were significantly lower in peritoneal macrophages and heart tissue from AR-knockout mice. LPS-induced activation of redox-sensitive signaling intermediates such as MAPKs, transcription factor NF-kB as well as Egr-1, a transcription regulator of mPGES-1, which in collaboration with COX-2 leads to the production of PGE2, were also significantly prevented by AR inhibition. Taken together, our results indicate that AR mediates LPS-induced inflammation by regulating AA metabolic pathway and thus provide novel role of AR inhibition in preventing inflammatory complications such as sepsis.

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Recent Development in the Field of Dual COX / 5-LOX Inhibitors

Cited by 27 publications

References 0 publications

Characterization and modulation of canine mast cell derived eicosanoids

Characterization and modulation of canine mast cell derived eicosanoids

Dual Acting Anti-Inflammatory Drugs

Inhibition of aldose reductase prevents endotoxin-induced inflammation by regulating the arachidonic acid pathway in murine macrophages

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