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Non-Steroidal Anti-Inflammatory Drugs
Published in Kate McCombe, Lara Wijayasiri, Paul Hatton, David Bogod, The Primary FRCA Structured Oral Examination Study Guide 2, 2017
Kate McCombe, Lara Wijayasiri, Paul Hatton, David Bogod
There are two types of COX when discussing NSAIDs: COX 1 and COX 2. COX 1 (constitutive) is found in most cells.COX 2 (inducible) is undetectable in most normal tissue but found in abundance in macrophages and other cells of inflammation. COX 2 catalyses the formation of inflammatory mediators and is therefore the enzyme that needs to be inhibited in order to decrease pain and inflammation. In theory, if COX 2 could be inhibited without affecting COX 1, symptoms would be improved with minimal or no side effects. In practice, this is not the case as COX 2 inhibitors still show the side-effect profile of non-specific agents.COX 3 discovered in 2002, it is an isoenzyme most likely to be a CNS variant of COX 1. It is the site of action of paracetamol.
Nonopioid and adjuvant analgesic agents
Published in Pamela E. Macintyre, Stephan A. Schug, Acute Pain Management, 2014
Pamela E. Macintyre, Stephan A. Schug
Despite its common and long history of use, the mechanisms underlying the antinociceptive effects of paracetamol are still not well understood. Originally believed to have only central effects, paracetamol is now thought to act both centrally and peripherally (Graham et al., 2013). It reduces prostaglandin synthesis from arachidonic acid via inhibition of the cyclooxygenase isoenzymes COX-1 and COX-2, but appears to be more selective for COX-2. However, it should not be termed a selective COX-2 inhibitor as it may inhibit COX-1 when arachidonic acid levels are low, and it also inhibits other oxidases (possibly COX-3 and/or peroxidase). Other possible mechanisms of action of paracetamol include an effect on central serotonergic (5-HT) pathways, a component of the descending inhibitory system of pain control, and on both the opioid and endocannabinoid systems (Graham et al., 2013). A potential role in the inhibition of nitric oxide synthetase with effects on the NMDA receptor is also debated. None of these hypotheses have been confirmed and the definitive mechanism of action underlying the analgesic effect of paracetamol remains unknown.
Chapter Paper 1 Answers
Published in James Day, Amy Thomson, Tamsin McAllister, Nawal Bahal, Get Through, 2014
James Day, Amy Thomson, Tamsin McAllister, Nawal Bahal
The cyclo-oxygenase enzymes exist as two main isoforms: COX-1 and COX-2. There also exists a COX-3 isoenzyme but this is a variant of COX-1 and has minimal activity in humans. COX-1 is the constitutive form that is responsible for the production of prostaglandins that form the gastric mucosa and control renal perfusion. COX-2 is induced at times of tissue injury as part of the inflammatory response. Agents that are selective for the COX-2 isoenzyme are rofecoxib, celecoxib, valdecoxib, parecoxib, eterocoxib and lumoricoxib. Meloxicam is preferential (rather than selective) for the COX-2 enzyme. When they were initially produced, the COX-2 inhibitors were favoured as they significantly reduce the incidence of gastrointestinal side effects when compared with non-selective COX inhibitors. However, the VIGOR study revealed an increased risk of coronary and cerebrovascular events with selective COX-2 inhibitors, which has limited their use.
Regular use of ibuprofen reduces rat penile prostaglandins and induces cavernosal fibrosis
Published in Drug and Chemical Toxicology, 2022
Abdel Aaal Elkamshoushi, Passainte Hassaan, Iman Nabil, Heba Ossama, Salma S. Omar
Ibuprofen exerts its therapeutic effect through inhibition of the cyclooxygenase (Cox) enzyme. Three isoforms of Cox are known: Cox-1, Cox-2, and Cox-3. Cox-1 is the constitutive form which is present in normal tissues, whereas Cox-2 is an inducible enzyme which is up-regulated because of tissue damage and inflammation. Cox-3 is exclusively found in the central nervous system, the nature of which remains unclear (Botting and Ayoub 2005, Suleyman et al. 2007). Both Cox-1 and Cox-2 catalyze the conversion of arachidonic acid to PG which are mediators of pain, fever, and inflammation (Barbagallo and Sacerdote 2019). It has been suggested that inhibition of the inflammatory-induced Cox-2 is responsible for the therapeutic effects of NSAIDs, while inhibition of the constitutive, cytoprotective Cox-1 causes the adverse effects. Ibuprofen is a nonselective balanced inhibitor of both constitutive Cox-1 and the inducible Cox-2 enzymes (Barbagallo and Sacerdote 2019, Qureshi and Dua 2020). Reported adverse effects of ibuprofen resulting from PG inhibition in different body systems include gastrointestinal ulceration, cardiovascular events, hepatic and renal toxicity, effects on blood pressure, and bleeding tendency (Ong et al. 2007).
(E)-5-hydroxy-7-methoxy-3-(2′-hydroxybenzyl)-4-chromanone isolated from Portulaca oleracea L. suppresses LPS-induced inflammation in RAW 264.7 macrophages by downregulating inflammatory factors
Published in Immunopharmacology and Immunotoxicology, 2021
Eunji Kang, Jae Eun Park, Youngwan Seo, Ji Sook Han
During the initial phase of the inflammatory response, PGE2 promotes tissue entry of neutrophils, macrophages, and mast cells from the bloodstream leading to swelling and edema at the site of infection or tissue injury [38]. PGE2 is an oxygenated metabolite of arachidonic acid, belonging to the prostanoid family of lipids, and is regulated by cyclooxygenase (COX) [39]. COX is a restrict enzyme of PGE2 biosynthesis, accounting for the conversion of arachidonic acid to PGH2 which is subsequently catalyzed by PGE synthase into PGE2 [40]. There are three types of COX, COX-1, COX-2, and COX-3, among which COX-2 has been reported to increase inflammation by overexpressing it at the site of inflammation [17,41–43]. On the other hand, this study showed that PGE2 levels exposed to LPS were upregulated, whereas treatment with the homoisoflavonoid, HM-chromanone, markedly inhibited PGE2 production. Similarly, pretreatment of Sappanone A, a homoisoflavonoid isolated from the heartwood of C. sappan, to RAW 264.7 cells have been reported to inhibit PGE2 production by concentration-dependently inhibiting LPS-induced COX-2 protein expression [44]. Thus, our results suggest that HM-chromanone may inhibit PGE2 synthesis, which may play an important role in inhibiting LPS-induced inflammation in RAW 264.7 macrophages.
Evaluation of Cytotoxic Potentials of Novel Cyclooxygenase-2 Inhibitor against ALL Lymphocytes and Normal Lymphocytes and Its Anticancer Effect through Mitochondrial Pathway
Published in Cancer Investigation, 2020
Ahmad Salimi, Marjan Aghvami, Mahsa Azami Movahed, Mohammad Hadi Zarei, Peyman Eshghi, Afshin Zarghi, Jalal Pourahmad
Cyclooxygenases (COXs) which are constitutively expressed in various cell types are essential enzymes for the conversion of arachidonic acid into prostaglandin (PG) G2 and subsequently to PGH2, which is a precursor for the synthesis of prostanoids, including PGs, prostacyclins and thromboxanes (1). Cyclooxygenases have three COX isozymes: COX-1, COX-2 and COX-3 (1). The subtypes of COX-2 enzymes are induced within inflammation, and the expansion of several types of cancer, such as prostate, breast, leukemia and colon cancer, is closely linked with chronic inflammation (2–7). Notably, the chronic use of COXs inhibitors have been shown to reduce the incidence and progression of several cancer (8). COX-2 isozymes are overexpressed in many cancer cells and are correlated with progression of cancer cells, as well as resistance of tumor cells to conventional therapies such as radiotherapy and chemotherapy (9). Recently, selective COX-2 inhibitors, like celecoxib showed a useful effect as chemopreventive agents and anticancer drugs against various cancers (10). Therefore, COX-2 inhibitors agents may prepare a potential therapeutic target for the therapy of cancer.