Anti-inflammatory drugs: new multitarget compounds to face an old problem. The dual inhibition concept

Celotti, F.; Laufer, Stefan

doi:10.1006/phrs.2000.0784

Cited by 145 publications

(112 citation statements)

References 79 publications

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“…Recently, emerging dual-acting antiinflammatory drugs, such as tepoxalin, tebufelone, and licofelone, which inhibit both the COX and the LOX pathways simultaneously, exert strong antiinflammatory activity without side effects like gastrointestinal damage (24). Thus, we inferred that the dual actions of wogonin on AA metabolism including the suppression of 5-LOX and induction of COX-2 expression could have potent pharmacological actions against alcohol-related gastric disease.…”

Section: Discussionmentioning

confidence: 92%

Preventive Effect of the Flavonoid, Wogonin, Against Ethanol-Induced Gastric Mucosal Damage in Rats

Park

Hahm

et al. 2004

Dig Dis Sci

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Whether wogonin (5,7-dihydroxy-8-methoxyflavone), a flavonoid originated from the root of Scutellaria baicalensis Georgi, which has been shown to have antiinflammatory and antitumor activities in various cell types, possesses a gastric cytoprotective effect was investigated in an ethanol-induced gastric damage model in rats. Ethanol administration alone induced evident gastric damage including gastric hemorrhages and edema, while this gastric damage was significantly attenuated by wogonin pretreatment (30 mg/kg B.W.) 1 hr before ethanol administration. As major protective mechanisms of wogonin on ethanol-induced gastric damage, we found that wogonin showed either antiinflammatory effects through dual actions on arachidonic acid metabolism, i.e., induction of prostaglandin D 2 and suppression of 5S-hydroxyeicosatetraenoic acid (5S-HETE), or preventive induction of profuse apoptosis in the stomach. Conclusively, the flavonoid wogonin could be used as a preventive agent of alcohol-induced gastropathy, whose actions were proven to be strong antiinflammation and apoptosis induction.

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Section: Discussionmentioning

confidence: 92%

Preventive Effect of the Flavonoid, Wogonin, Against Ethanol-Induced Gastric Mucosal Damage in Rats

Park

Hahm

et al. 2004

Dig Dis Sci

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“…Their combination with NSAID may reduce adverse renal effects. Several distinct agents with balanced inhibitory actions on the COX and lipoxygenase pathways also have been synthesized and are in various phases of preclinical or clinical development (123,124), and recently, a clinical trial indicated that the lipoxygenase/COX inhibitor licofelone could provide as effective pain relief as celecoxib but with less edema (125).…”

Section: Effects Of Cox-2 Inhibitors In Proteinuric Statesmentioning

confidence: 99%

Update on Cyclooxygenase-2 Inhibitors

Harris

Breyer

2006

Clinical Journal of the American Society of Nephrology

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Nonsteroidal anti-inflammatory drugs represent the most commonly used medications for the treatment of pain and inflammation, but numerous well-described side effects can limit their use. Cyclooxygenase-2 (COX-2) inhibitors were initially touted as a therapeutic strategy to avoid not only the gastrointestinal but also the renal and cardiovascular side effects of nonspecific nonsteroidal anti-inflammatory drugs. However, in the kidney, COX-2 is constitutively expressed and is highly regulated in response to alterations in intravascular volume. COX-2 metabolites have been implicated in mediation of renin release, regulation of sodium excretion, and maintenance of renal blood flow. This review summarizes the current state of knowledge about both renal and cardiovascular side effects that are attributed to COX-2 selective inhibitors.Clin J Am Soc Nephrol 1: 236 -245, 2006236 -245, . doi: 10.2215 N onsteroidal anti-inflammatory drugs (NSAID) are the most commonly used class of medications for the treatment of pain and inflammation and represent one of the most common classes of medications used worldwide, with an estimated usage of Ͼ30 million per day (1). Nonselective NSAID inhibit both constitutive cyclooxygenase-1 (COX-1) and inducible cyclooxygenase-2 (COX-2), the rate-limiting enzymes that are involved in production of prostaglandins and thromboxane. In addition to their role in inflammation, prostaglandins are important regulators of vascular tone, salt and water balance, and renin release, and nonselective NSAID exhibit adverse effects, including salt retention and reduced GFR, which may elevate BP or make pre-existing hypertension worse (2). It has been estimated that as many as 2.5 million Americans experience NSAID-mediated renal effects yearly (3). Risk factors that predispose to NSAID-induced renal functional alterations include age Ͼ65 yr, cardiovascular disease, diabetes, male gender, high NSAID dosage, and concurrent use of other nephrotoxic drugs (3). Up to 20% of patients who take nonselective NSAID and have more than one of these risk factors may manifest alterations in renal function.In addition to renal side effects, nonselective NSAID have long been known to predispose to gastrointestinal (GI) toxicity. It has been estimated that one third of patients who taking long-term nonselective NSAID develop endoscopically proven gastric or duodenal ulcers (4). The risk for serious bleeding from these lesions is somewhat lower, with approximately 100,000 hospitalizations for GI complications of NSAID (5). One study estimated that nonselective NSAID-induced GI abnormalities constitute the 15th leading cause of death in the United States (6). The premise that COX-1 performs cellular "housekeeping" functions for normal physiologic activity and is the predominant isoform expressed in platelets and the GI tract, whereas COX-2 acts at inflammatory sites, led to the development of COX-2 selective inhibitors. It also was originally hypothesized that the renal effects of nonselective NSAID were also linked to COX-...

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“…Therefore, medications that inhibit both COX-1/2 and 5-LOX pathways are believed to be superior to conventional NSAIDs since they could produce a synergistic effect and achieve optimal anti-inflammatory activity by blocking the production of both leukotrienes and prostaglandins (Celotti & Laufer, 2001;Martel-Pelletier et al, 2003). This is supported by a significant reduction of collagen-induced arthritis in animal models upon concomitant administration of NSAID and leukotriene synthesis inhibitors (MartelPelletier et al, 2003;Nickerson-Nutter & Medvedeff, 1996).…”

Section: Introductionmentioning

confidence: 99%