Comparative Adverse Effects Of Cox-1 and Cox-2 Inhibitors in Rat Liver: An Experimental Study."

Cyclooxygenase-2 selective inhibitors (COXIBs) were developed with the prime object of minimizing gastrointestinal adverse effects, which are seen with the use of traditional nonsteroidal anti-inflammatory drugs (NSAIDs). Their long-term use is limited by the development of hypertension, edema, and congestive heart failure in a significant proportion of patients. NSAIDs block the activity of both COX isozymes, COX-1 and COX-2, which mediate the enzymatic conversion of arachidonate to prostaglandin H2(PGH2) and other prostaglandin (PG) metabolites. It is well established that the cardiovascular profile of COX-2 inhibitors can be accounted for by inhibition of COX-dependent PG synthesis. Following the COX-mediated synthesis of PGH2from arachidonate, PGH2is metabolized to one of at least five bioactive PGs, including PGE2, PGI2, PGF2, PGD2, or thromboxane A2(TXA2). These prostanoids have pleiotropic cardiovascular effects, altering platelet function and renal function, and they are acting either as vasodilators or vasoconstrictors. Although COX-1 and COX-2 exhibit similar biochemical activity in converting arachidonate to PGH2in vitro, the ultimate prostanoids they producein vivomay be different due to differential regulation of COX-1 and COX-2, tissue distribution, and availability of the prostanoid synthases. PGs have been established as being critically involved in mitigating hypertension, helping to maintain medullary blood flow (MBF), promoting urinary salt excretion, and preserving the normal homeostasis of thrombosis, and the researchers found that the use of COX-2 inhibitors caused many serious complications in altering the normal body homeostasis. The purpose of the present research is to explain briefly the side effects of COX-2 inhibitors on the renal and cardiovascular system.

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Mitochondrial toxicity of selective COX-2 inhibitors via inhibition of oxidative phosphorylation (ATP synthesis) in rat liver mitochondria

Toxicology in Vitro ◽

10.1016/j.tiv.2015.12.003 ◽

2016 ◽

Vol 32 ◽

pp. 26-40 ◽

Cited By ~ 6

Author(s):

Muzeeb Syed ◽

Christian Skonberg ◽

Steen Honoré Hansen

Keyword(s):

Oxidative Phosphorylation ◽

Rat Liver ◽

Atp Synthesis ◽

Liver Mitochondria ◽

Rat Liver Mitochondria ◽

Mitochondrial Toxicity ◽

Cox 2 ◽

Cox 2 Inhibitors

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Cyclooxygenase-2 plays a significant role in regulating the tone of the fetal lamb ductus arteriosus

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1999.276.3.r913 ◽

1999 ◽

Vol 276 (3) ◽

pp. R913-R921 ◽

Cited By ~ 13

Author(s):

Ronald I. Clyman ◽

Pierre Hardy ◽

Nahid Waleh ◽

Yao Qi Chen ◽

Françoise Mauray ◽

...

Keyword(s):

Significant Role ◽

Ductus Arteriosus ◽

Late Gestation ◽

Relative Contribution ◽

Cox Inhibitor ◽

Fetal Lamb ◽

Cox 2 ◽

Cox 2 Inhibitors ◽

Cox 1

Nonselective cyclooxygenase (COX) inhibitors are potent tocolytic agents but have adverse effects on the fetal ductus arteriosus. We hypothesized that COX-2 inhibitors may not affect the ductus if the predominant COX isoform is COX-1. To examine this hypothesis, we used ductus arteriosus obtained from late-gestation fetal lambs. In contrast to our hypothesis, fetal lamb ductus arteriosus expressed both COX-1- and COX-2-immunoreactive protein (by Western analysis). Although COX-1 was found in both endothelial and smooth muscle cells, COX-2 was found only in the endothelial cells lining the ductus lumen (by immunohistochemistry). The relative contribution of COX-1 and COX-2 to PGE2 synthesis was consistent with the immunohistochemical results: in the intact ductus, PGE2 formation was catalyzed by both COX-1 and COX-2 in equivalent proportions; in the endothelium-denuded ductus, COX-2 no longer played a significant role in PGE2 synthesis. NS-398, a selective inhibitor of COX-2, was 66% as effective as the selective COX-1 inhibitor valeryl salicylate and the nonselective COX inhibitor indomethacin in causing contraction of the ductus in vitro. At this time, caution should be used when recommending COX-2 inhibitors for use in pregnant women.

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Involvement of cyclooxygenase 2 (COX-2) in intrinsic tone of isolated guinea pig

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y95-215 ◽

1995 ◽

Vol 73 (11) ◽

pp. 1561-1567 ◽

Cited By ~ 21

Author(s):

L. Charette ◽

C. Misquitta ◽

J. Guay ◽

D. Riendeau ◽

T. R. Jones

Keyword(s):

Guinea Pig ◽

Time Course ◽

Cyclooxygenase 2 ◽

Maximal Response ◽

Pharmacological Agents ◽

Cyclooxygenase 1 ◽

Inflammatory Drugs ◽

Cox 2 ◽

Cox 2 Inhibitors ◽

Cox 1

Indomethacin and related nonsteroidal anti-inflammatory drugs relax prostanoid-dependent intrinsic tone of isolated guinea pig trachea by inhibiting cyclooxygenase (COX). Recently, a second isoform of COX (COX-2) was discovered, which differed from COX-1 with respect to protein structure, transcriptional regulation, and susceptibility to inhibition by pharmacological agents. It is now known that indomethacin nonselectively inhibits COX-1 and COX-2, whereas NS-398 is a selective inhibitor of COX-2. In the present study we compared the activity of a selective (NS-398) and nonselective (indomethacin) COX-2 inhibitor on intrinsic tone of isolated guinea pig trachea. NS-398 ≥ indomethacin produced a reversal of intrinsic tone with a similar concentration-dependent (10 nM to 1 μM) time course (Tmax approximately 20–45 min), potency (EC50 1.7 and 5.6 nM, respectively), and maximal response. Contractions to cholinergic nerve stimulation (45 V, 0.5 ms, 0.1–32 Hz) and histamine were similarly modulated in tissues relaxed with the selective or nonselective COX-2 inhibitors. Immunoblot analyses showed that COX-2 protein synthesis was induced in both the cartilage and smooth muscle portions of the trachea during changes in intrinsic tone. These findings are consistent with pharmacological results and provide the first demonstration that prostanoid tone in isolated guinea pig trachea is dependent on COX-2 activity. The results also suggest that the activity of indomethacin in this preparation is likely related to COX-2 inhibition.Key words: cyclooxygenase 2, relaxation, guinea pig trachea, cyclooxygenase 1.

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Synthesis, biological evaluation and molecular docking studies of stellatin derivatives as cyclooxygenase (COX-1, COX-2) inhibitors and anti-inflammatory agents

Bioorganic & Medicinal Chemistry Letters ◽

10.1016/j.bmcl.2011.01.116 ◽

2011 ◽

Vol 21 (6) ◽

pp. 1612-1616 ◽

Cited By ~ 38

Author(s):

Raju Gautam ◽

Sanjay M. Jachak ◽

Vivek Kumar ◽

C. Gopi Mohan

Keyword(s):

Molecular Docking ◽

Docking Studies ◽

Biological Evaluation ◽

Molecular Docking Studies ◽

Cox 2 ◽

Anti Inflammatory ◽

Cox 2 Inhibitors ◽

Cox 1

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New indomethacin analogs as selective COX‐2 inhibitors: Synthesis, COX‐1/2 inhibitory activity, anti‐inflammatory, ulcerogenicity, histopathological, and docking studies

Archiv der Pharmazie ◽

10.1002/ardp.202000328 ◽

2020 ◽

Author(s):

Khaled R. A. Abdellatif ◽

Eman K. A. Abdelall ◽

Heba A. H. Elshemy ◽

El‐Shaymaa El‐Nahass ◽

Maha M. Abdel‐Fattah ◽

...

Keyword(s):

Inhibitory Activity ◽

Docking Studies ◽

Cox 2 ◽

Anti Inflammatory ◽

Cox 2 Inhibitors ◽

Cox 1

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Chlorinated cobalt alkyne complexes derived from acetylsalicylic acid as new specific antitumor agents

Dalton Transactions ◽

10.1039/c7dt04790h ◽

2018 ◽

Vol 47 (12) ◽

pp. 4341-4351 ◽

Cited By ~ 10

Author(s):

Victoria Obermoser ◽

Daniel Baecker ◽

Carina Schuster ◽

Valentin Braun ◽

Brigitte Kircher ◽

...

Keyword(s):

Antitumor Agents ◽

Tumor Cell Lines ◽

Growth Inhibitory ◽

Cox 2 ◽

Alkyne Complexes ◽

Inhibitory Potential ◽

Cox 2 Inhibitors ◽

Ht 29 ◽

Cox 1 ◽

Mcf 7

Chlorine-substituted [(prop-2-ynyl)-2-acetoxybenzoate]dicobalthexacarbonyl complexes are selective COX-2 inhibitors with growth-inhibitory potential against COX-1/2 containing MDA-MB-231 and HT-29 tumor cell lines. The metabolic activity of non-tumorigenic HS-5 cells and COX-1/2-independent MCF-7 cells is not influenced.

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Synthesis of Novel Benzodifuranyl; 1,3,5-Triazines; 1,3,5-Oxadiazepines; and Thiazolopyrimidines Derived from Visnaginone and Khellinone as Anti-Inflammatory and Analgesic Agents

Molecules ◽

10.3390/molecules25010220 ◽

2020 ◽

Vol 25 (1) ◽

pp. 220 ◽

Cited By ~ 6

Author(s):

Ameen Ali Abu-Hashem ◽

Sami A Al-Hussain ◽

Magdi E. A. Zaki

Keyword(s):

Sodium Ethoxide ◽

Standard Drug ◽

Chemical Structures ◽

Cyclooxygenase 1 ◽

Analgesic Agents ◽

Cox 2 ◽

Anti Inflammatory ◽

New Compounds ◽

Cox 2 Inhibitors ◽

Cox 1

Novel (4-methoxy or 4,8-dimethoxy)-3-methyl-N-(6-oxo-2-thioxo-1,2,3, 6-tetrahydro- pyrimidin-4-yl) benzo [1,2-b: 5, 4-b’] difuran-2-carboxamide (5a–b) has been synthesized by the reaction of visnagenone–ethylacetate (2a) or khellinone–ethylacetate (2b) with 6-aminothiouracil in dimethylformamide or refluxing of benzofuran-oxy-N-(2-thioxopyrimidine) acetamide (4a–b) in sodium ethoxide to give the same products (5a,b) in good yields. Thus, compounds 5a–b are used as an initiative to prepare many new heterocyclic compounds such as 2-(4-(3-methylbenzodifuran- 2-carbox-amido) pyrimidine) acetic acid (6a–b), N-(thiazolo[3, 2-a]pyrimidine)-3-methylbenzo- difuran-2-carboxamide (7a–b), N-(2-thioxopyrimidine)-methylbenzodifuran-2-carbimidoylchloride (8a–b), N-(2-(methyl-thio) pyrimidine)-3-methylbenzodifuran-2-carbimidoylchloride (9a–b), N-(2, 6 -di(piperazine or morpholine)pyrimidine)-1-(3-methylbenzodifuran)-1-(piperazine or morpholine) methanimine(10a–d), 8-(methylbenzodifuran)-thiazolopyrimido[1,6-a][1,3,5]triazine-3,5-dione (11a –b), 8-(3-methyl benzodifuran)-thiazolopyrimido[6,1-d][1,3,5]oxadiazepine-trione (12a–b), and 2,10 -di(sub-benzylidene)-8-(3-methylbenzodifuran)-thiazolopyrimido[6,1-d][1,3,5]oxadiazepine-3,5,11- trione (13a–f). All new chemical structures were illustrated on the basis of elemental and spectral analysis (IR, NMR, and MS). The new compounds were screened as cyclooxygenase-1/ cyclooxygenase-2 (COX-1/COX-2) inhibitors and had analgesic and anti-inflammatory activities. The compounds 10a–d and 13a–f had the highest inhibitory activity on COX-2 selectivity, with indices of 99–90, analgesic activity of 51–42% protection, and anti-inflammatory activity of 68%–59%. The inhibition of edema for the same compounds, 10a–d and 13a–f, was compared with sodium diclofenac as a standard drug.

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