COX-1 and COX-3 inhibitors

doi:10.1016/S0049-3848(03)00411-0

Thrombosis Research

Volume 110, Issues 5–6, 15 June 2003, Pages 269-272

https://doi.org/10.1016/S0049-3848(03)00411-0 Get rights and content

Abstract

Low doses of aspirin reduce both pain and fever, whereas the anti-inflammatory action of aspirin requires a much higher dose. It is possible that inhibition of cyclooxygenase (COX)-1 is the major action of aspirin involved in its analgesic and antipyretic effects, and inhibition of COX-2 is responsible for its anti-inflammatory action. We compared the analgesic effects of an aspirin-like drug (diclofenac) and a centrally acting analgesic (paracetamol) in the mouse stretching test and confirmed that the analgesic action of the aspirin-like drug was peripheral.

Two possible sites have been postulated for the antipyretic action of non-steroid anti-inflammatory drugs; (a) inhibition of COX in endothelial cells of hypothalamic blood vessels or (b) inhibition of COX synthesising prostaglandins near sensory receptors of sub-diaphragmatic vagal afferents. The antipyretic action of aspirin may be mediated by inhibition of COX-3 in hypothalamic endothelial cells or by inhibition of COX-1 localised close to sensory receptors of peripheral vagal afferents. It is also possible that both enzymes are involved in the antipyretic action of aspirin. Whereas lipopolysaccharide (LPS)-induced fever is attenuated in COX-2 gene-deleted mice, suggesting that COX-2 is responsible for this type of fever, the COX-1 gene may also be important in temperature regulation and in mediating the pyresis that occurs in the absence of infection.

Section snippets

COX-1 and COX-3 in analgesia

Aspirin analgesia was studied by Lim et al. [2] in 1964. In an elegant cross circulation experiment in dogs, Lim et al. showed that aspirin produced its analgesic action peripherally rather than in the central nervous system (Fig. 1). Bradykinin was injected as the noxious stimulus into the spleen of the dog receiving a splenic circulation from another anaesthetised donor dog. The bradykinin injection stimulated pain fibres and caused a rise of blood pressure of the recipient animal. Morphine

COX-1, COX-2 and COX-3 in fever

The mechanisms of fever are complex and poorly understood. Both aspirin-like drugs and paracetamol are potent antipyretic agents but it is difficult to accept that they can act by the same mechanism. Lipopolysaccharide (LPS)-induced fever is the model of fever that has been most frequently studied, but this type of fever follows a different course in different species. Rabbits and guinea pigs respond to an injection of LPS with a fast onset, long lasting fever, while LPS either has no effect or

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Aspirin in retrieving the inactivated catalase to active form: Displacement of one inhibitor with a protective agent
2019, International Journal of Biological Macromolecules
Citation Excerpt :
It was shown that this drug is able to interact with various proteins such as transferrin, albumin and immunoglobulin based on the acetylation process [1,2]. Aspirin could acetylate the serine residues in different targets such as cyclooxygenases, which is related to the reduction of prostaglandin synthesis [3–5]. Furthermore, it is revealed that aspirin has capability to affect the binding process of other drugs or compounds on targets.
Aspirin as a potential drug is able to bind to different targets and also could affect on the binding process of other ligands. In the present work, aspirin was considered as a protective agent to retrieve the inactivated catalase by farnesiferol C (FC) through displacement manner. The catalytic assessment revealed that aspirin is able to remarkably retrieve the activity of FC-catalase from 4.2 ± 0.2% to 98 ± 0.1% compare to the control sample. Furthermore, displacement study and CD spectroscopy indicated that aspirin could reduce the stability of FC-catalase complex. Based on the obtained data, it is shown that the binding of aspirin to catalase led to decrease the affinity of catalase to the inhibitor. The releasing analysis of FC from the complex showed that the dissociation constant (K_d) of FC-catalase was increased, considerably from 8.9 ± 0.2 μM to 256 ± 01 μM in the presence of aspirin at 298 K. Also, molecular simulation proved the instability of FC-catalase following the binding of aspirin to the complex.
Design, synthesis and biological evaluation of hybrid nitroxide-based non-steroidal anti-inflammatory drugs
2018, European Journal of Medicinal Chemistry
Dual-acting hybrid anti-oxidant/anti-inflammatory agents were developed employing the principle of pharmacophore hybridization. Hybrid agents were synthesized by combining stable anti-oxidant nitroxides with conventional non-steroidal anti-inflammatory drugs (NSAIDs). Several of the hybrid nitroxide-NSAID conjugates displayed promising anti-oxidant and anti-inflammatory effects on two Non-Small Cell Lung Cancer (NSCLC) cells (A549 and NCI-H1299) and in ameliorating oxidative stress induced in 661 W retinal cells. One ester-linked nitroxide-aspirin analogue (27) delivered better anti-inflammatory effects (cyclooxygenase inhibition) than the parent compound (aspirin), and also showed similar reactive oxygen scavenging activity to the anti-oxidant, Tempol. In addition, a nitroxide linked to the anti-inflammatory drug indomethacin (39) significantly ameliorated the effects of oxidative stress on 661 W retinal neurons at efficacies greater or equal to the anti-oxidant Lutein. Other examples of the hybrid conjugates displayed promising anti-cancer activity, as demonstrated by their inhibitory effects on the proliferation of A549 NSCLC cells.
Cleavage and polyadenylation specific factor 4 targets NF-κB/cyclooxygenase-2 signaling to promote lung cancer growth and progression
2016, Cancer Letters
Citation Excerpt :
COX-1 has been found to be constitutively expressed in most normal cells and exerts housekeeping functions through participating in the body's normal physiological processes [8–10]. COX-3 is the splice variant of COX-1, and it is newly discovered [7,11–13]. COX-2 is hardly detected due to its extremely low level in normal cells.
Overexpression of cyclooxygenase 2 (COX-2) is frequently found in early and advanced lung cancers. However, the precise regulatory mechanism of COX-2 in lung cancers remains unclear. Here we identified cleavage and polyadenylation specific factor 4 (CPSF4) as a new regulatory factor for COX-2 and demonstrated the role of the CPSF4/COX-2 signaling pathway in the regulation of lung cancer growth and progression. Overexpression or knockdown of CPSF4 up-regulated or suppressed the expression of COX-2 at mRNA and protein levels, and promoted or inhibited cell proliferation, migration and invasion in lung cancer cells. Inhibition or induction of COX-2 reversed the CPSF4-mediated regulation of lung cancer cell growth. Cancer cells with CPSF4 overexpression or knockdown exhibited increased or decreased expression of p-IKKα/β and p-IκBα, the translocation of p50/p65 from the cytoplasm to the nucleus, and the binding of p65 on COX-2 promoter region. In addition, CPSF4 was found to bind to COX-2 promoter sequences directly and activate the transcription of COX-2. Silencing of NF-κB expression or blockade of NF-κB activity abrogated the binding of CPSF4 on COX-2 promoter, and thereby attenuated the CPSF4-mediated up-regulation of COX-2. Moreover, CPSF4 was found to promote lung tumor growth and progression by up-regulating COX-2 expression in a xenograft lung cancer mouse model. CPSF4 overexpression or knockdown promoted or inhibited tumor growth in mice, while such regulation of tumor growth mediated by CPSF4 could be rescued through the inhibition or activation of COX-2 signaling. Correspondingly, CPSF4 overexpression or knockdown also elevated or attenuated COX-2 expression in tumor tissues of mice, while treatment with a COX-2 inducer LPS or a NF-κB inhibitor reversed this elevation or attenuation. Furthermore, we showed that CPSF4 was positively correlated with COX-2 levels in tumor tissues of lung cancer patients. Simultaneous high expression of CPSF4 and COX-2 proteins predicted poor prognosis of patients with lung cancers. Our results therefore demonstrated a novel mechanism for the transcriptional regulation of COX-2 by CPSF4 in lung cancer, and also offer a potential therapeutic target for lung cancers bearing aberrant activation of CPSF4/COX-2 signaling.
Targeting arachidonic acid pathway by natural products for cancer prevention and therapy
2016, Seminars in Cancer Biology
Citation Excerpt :
COX-1 and its products PGs maintain the integrity of the mucosal epithelium in the stomach and intestine and their inhibition, as happens with the conventional NSAIDs, leads to gastric damage, hemorrhage, and ulceration [32,33]. COX-3 is the third isoform of COX, encoded by the same COX-1 gene but alternatively spliced, is not functional in humans [34,35]. COX enzymes initially convert AA to PGH2 and specific downstream enzymes isomerize PGH2 to prostacyclin (PGI2), prostaglandins D2, E2, or F2α, or TXA2 [6].
Arachidonic acid (AA) pathway, a metabolic process, plays a key role in carcinogenesis. Hence, AA pathway metabolic enzymes phospholipase A₂s (PLA₂s), cyclooxygenases (COXs) and lipoxygenases (LOXs) and their metabolic products, such as prostaglandins and leukotrienes, have been considered novel preventive and therapeutic targets in cancer. Bioactive natural products are a good source for development of novel cancer preventive and therapeutic drugs, which have been widely used in clinical practice due to their safety profiles. AA pathway inhibitory natural products have been developed as chemopreventive and therapeutic agents against several cancers. Curcumin, resveratrol, apigenin, anthocyans, berberine, ellagic acid, eugenol, fisetin, ursolic acid, [6]-gingerol, guggulsteone, lycopene and genistein are well known cancer chemopreventive agents which act by targeting multiple pathways, including COX-2. Nordihydroguaiaretic acid and baicalein can be chemopreventive molecules against various cancers by inhibiting LOXs. Several PLA₂s inhibitory natural products have been identified with chemopreventive and therapeutic potentials against various cancers. In this review, we critically discuss the possible utility of natural products as preventive and therapeutic agents against various oncologic diseases, including prostate, pancreatic, lung, skin, gastric, oral, blood, head and neck, colorectal, liver, cervical and breast cancers, by targeting AA pathway. Further, the current status of clinical studies evaluating AA pathway inhibitory natural products in cancer is reviewed. In addition, various emerging issues, including bioavailability, toxicity and explorability of combination therapy, for the development of AA pathway inhibitory natural products as chemopreventive and therapeutic agents against human malignancy are also discussed.
Sublingual ketorolac and sublingual piroxicam are equally effective for postoperative pain, trismus, and swelling management in lower third molar removal
2012, Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology
Lower third molar removal provides a clinical model for studying analgesic drugs. The present study's aim was to compare the clinical efficacy of sublingual ketorolac and sublingual piroxicam in managing pain, trismus and swelling after lower third molar extraction in adult volunteers.
In this double-blinded, randomized, crossover investigation, 47 volunteers received for 4 days ketorolac sublingually (10 mg 4 times daily) and piroxicam sublingually (20 mg once daily) during 2 separate appointments after lower third molar extraction of symmetrically positioned lower third molars. A surgeon evaluated objective parameters (surgery duration, mouth opening, rescue analgesic medication, and facial swelling) and volunteers documented subjective parameters (postoperative pain and global evaluation), comparing postoperative results for a total of 7 days after surgery. The means of the objective and subjective parameters were compared for statistical significance (P < .05).
Volunteers reported low pain scores during the postoperative period when treated with either sublingual ketorolac or piroxicam. Also, volunteers ingested similar amounts of analgesic rescue medication (paracetamol) when they received either drug sublingually (P > .05). Additionally, values for mouth openings measured just before surgery and immediately after suture removal 7 days later were similar among volunteers (P > .05), and the type of nonsteroidal antiinflammatory drug (NSAID) used in this study showed no significant differences between swellings on the second or seventh days after surgery (P > .05).
Pain, trismus, and swelling after lower third molar extraction, independent of surgical difficulty, were successfully controlled by sublingual ketorolac (10 mg 4 times daily) or sublingual piroxicam (20 mg once daily), and no significant differences were observed between the NSAIDs evaluated.
An Overview of Arachidonic Acid Metabolic Pathway and Recent Updates on a Few Heterocyclic Derivatives showing COX-2 Inhibition
2023, International Journal of Drug Delivery Technology

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Regular ArticleCOX-1 and COX-3 inhibitors

Abstract

Section snippets

COX-1 and COX-3 in analgesia

COX-1, COX-2 and COX-3 in fever

Life Sci.

Brain Res.

Brain Res.

Site of action of narcotic and non-narcotic analgesics determined by blocking bradykinin-evoked visceral pain

Arch. Int. Pharmacodyn.

The abdominal constriction response and its suppression by analgesic drugs in the mouse

Br. J. Pharmacol. Chemother.

Selectivity of nonsteroidal anti-inflammatory drugs as inhibitors of constitutive and inducible cyclooxygenase

Proc. Natl. Acad. Sci. U. S. A.

Nociception in cyclooxygenase isozyme-deficient mice

Proc. Natl. Acad. Sci. U. S. A.

The role of prostaglandins in the nociceptive response induced by intraperitoneal injection of zymosan in mice

Br. J. Pharmacol.

Regular Article
COX-1 and COX-3 inhibitors