Adverse Cardiovascular Effects of the Coxibs

Dogné, Jean-Michel; Supuran, Claudiu T.; Praticò, Domenico

doi:10.1021/jm0402059

Cited by 310 publications

(115 citation statements)

References 27 publications

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“…An interesting aspect of these drugs is their potential use in treating Alzheimers disease and certain forms of cancer [3] [4]. The drawback in their use is that they increase the risk of heart attack and stroke [5] [6]. Blood vessels and platelets are the major targets of prostanoids such as prostacycline PGI 2 , prostaglandin PGE 2 , and thromboxane TxA 2 in the cardiovascular system.…”

mentioning

confidence: 99%

Nitrooxymethyl‐Substituted Analogues of Celecoxib: Synthesis and Pharmacological Characterization

Boschi

Lazzarato

Rolando

et al. 2009

Chemistry & Biodiversity

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Nitrooxymethyl-substituted analogues of celecoxib were synthesized and tested for their cyclooxygenase (COX)-inhibiting, vasodilator, and anti-aggregatory activities, as well as for their metabolic stability in human serum and whole blood. The results showed their potency and selectivity in inhibiting the COX isoforms, evaluated in whole human blood, as well as their anti-aggregatory activity to depend closely on the position at which the NO-donor moiety is introduced. All products dilated rat aorta strips precontracted with phenylephrine in a dose-dependent manner through a cGMP-dependent mechanism. They were stable in human serum while, in blood, they were metabolically transformed, principally to the related alcohols.Introduction. -Cyclooxygenase (COX) is one of the key enzymes implicated in the transformation of arachidonic acid into prostanoids. It exists in at least two isoforms, COX-1 and COX-2. The former is prevalently a constitutive and the latter an inducible isoform. Selective blocking of these isoforms induces specific pharmacological effects which can be exploited in therapy [1]. COX-2-Selective inhibitors (Coxibs) are a new class of drugs recently introduced into the market [2]; they induce anti-inflammatory effects without the gastrotoxic side-effects typical of the classical non-steroidal antiinflammatory drugs (NSAIDs), which are nonselective COX inhibitors. An interesting aspect of these drugs is their potential use in treating Alzheimers disease and certain forms of cancer [3] [4]. The drawback in their use is that they increase the risk of heart attack and stroke [5] [6]. Blood vessels and platelets are the major targets of prostanoids such as prostacycline PGI 2 , prostaglandin PGE 2 , and thromboxane TxA 2 in the cardiovascular system. The proaggregatory and vasoconstrictor TxA 2 is mainly synthesized via COX-1 in the platelets, while vasodilator (PGI 2 , PGE 2 ) and antiplatelet (PGI 2 ) compounds are synthesized mainly in the vascular endothelium. A strategy to improve the benefit -risk profiles of these drugs is to design a multi-target drug by combining COX-2-selective inhibition with nitric oxide (NO)-dependent activities. NO displays a variety of effects in the cardiovascular system, including vasodilation, inhibition of platelet aggregation, modulation of platelet and leukocytes adherence to vessels, and inhibition of smooth muscle cell proliferation [7]. Examples of this type of approach have already been reported [8] [9] including by our group [10] [11]. As a development of our work in this field, we now describe the synthesis and structural characterization of a new series of NO-donor COX-2 inhibitors obtained by introducing NO-donor nitrooxy functions into the well-known selective COX-2

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mentioning

confidence: 99%

Nitrooxymethyl‐Substituted Analogues of Celecoxib: Synthesis and Pharmacological Characterization

Boschi

Lazzarato

Rolando

et al. 2009

Chemistry & Biodiversity

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“…However, the use of indomethacin is restricted because of its high incidence of ulcerogenic side effects. Several selective COX-2 inhibitors were introduced for clinical use and displayed remarkable anti-inflammatory properties and reduced gastric toxicity compared with indomethacin; however, severe cardiovascular side effects have been detected after long-term use (Dogne et al, 2005). Recent studies have investigated the use of indomethacin combined with an antioxidant devoid of ulcerogenic side effects, and have shown that the antiinflammatory properties were retained (Bandgar et al, 2011;Bhandari et al, 2010;Doulgkeris et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

The role of cyclooxygenase-derived oxidative stress in surgically induced lymphedema in a mouse tail model

Chang

Uen

Chou

et al. 2013

Pharmaceutical Biology

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Context: Oxidative stress may contribute to lymphedema and subsequent tissue damage. However, the causal role of oxidative stress in lymphedema remains unclear. Objective: We attempted to detect and identify the free radicals formed in lymphedema fluid and assessed the protective mechanisms and effects of specific enzyme inhibitors and natural antioxidants. Materials and methods: To study the level of postsurgical oxidative stress with lymphedema in a mouse tail model, we used an electron spin resonance (ESR) method and an ascorbyl radical's ESR spectrum as an oxidative stress biomarker. The drug-treatment group received an i.p. injection with indomethacin (2 mg/kg), baicalein (15 mg/kg), MK-886 (3 mg/kg), zileuton (6.25 mg/kg), diphenyleneiodonium (DPI; 1 mg/kg), sulforaphane (30 mg/kg), oryzanol (30 mg/ kg) or sesamol (30 mg/kg) once daily for 14 d from the day of operation. All animals were sacrificed on day 14. Results: Administration of indomethacin, sulforaphane, oryzanol and sesamol significantly suppressed both the tail volume (56.9%, 77.8%, 72.2% and 38.1% inhibition, respectively, p50.01) and ascorbyl radical signals (31.4%, 54.5%, 79.3% and 57.1% inhibition, respectively, p50.01), compared with the control mice. No significant differences were found between any of the baicalein, MK-886, or zileuton groups compared with the control. DPI suppressed the tail volume (25.9% inhibition, p50.01) but not the ascorbyl radical signals. Conclusion: This study showed that COX-derived oxidative stress plays a major role in the pathological mechanisms of surgically induced lymphedema. Indomethacin, sulforaphane, oryzanol and sesamol exhibit potent protective properties against surgically induced lymphedema.

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“…Based upon a number of selective COX-2 inhibitors such as celecoxib (4), rofecoxib (5) and valdecoxib (6) were developed as safer NSAIDs with improved gastric safety profile. However, the recent market removal of some COXIBs such as rofecoxib and valdecoxib due to their adverse cardiovascular side effects clearly encourages the researchers to explore and evaluate alternative templates with COX-2 inhibitory activity (Dogné et al, 2005.…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis and biological evaluation of some novel indole derivatives as selective COX-2 inhibitors

2017

J App Pharm Sci

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A new group of (4-substitutedphenyl)(3-((2-(4-substitutedphenyl)hydrazono)methyl)-1H-indol-1-yl)methanone derivatives 13a-f as indomethacin analogs was synthesized through N-benzoylation of indole-3-cabaldehyde with the appropriate benzoyl fragment followed by reaction with substituted phenylhydrazine. All the synthesized compounds were evaluated in vitro for COX-1/COX-2 inhibitory activity and in vivo for their antiinflammatory activity in comparison with the parent drug indomethacin. Compounds 13a,b,d,e which contain SO2Me or SO2NH2 group as a pharmacophore of COX-2, exhibited the most anti-inflammatory and selectivity actives so, they were more evaluated by calculating their ED50% doses and ulcerogenic indices to ensure their gastric safety margin relative to indomethacin.

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Adverse Cardiovascular Effects of the Coxibs

Cited by 310 publications

References 27 publications

Nitrooxymethyl‐Substituted Analogues of Celecoxib: Synthesis and Pharmacological Characterization

Nitrooxymethyl‐Substituted Analogues of Celecoxib: Synthesis and Pharmacological Characterization

The role of cyclooxygenase-derived oxidative stress in surgically induced lymphedema in a mouse tail model

Design, Synthesis and biological evaluation of some novel indole derivatives as selective COX-2 inhibitors

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