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Therapeutic Use of Carbonic Anhydrase Inhibitors and Their Multiple Drug Interactions
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Andrea Angeli, Claudiu T. Supuran
Celecoxib is the first selective COX-2 inhibitor to be approved for clinical practice in the treatment of patients with rheumatoid arthritis, osteoarthritis and for management of the pain of these conditions (Skarke et al., 2012). However, this class is putative gastrointestinal safety advantages compared with other NSAIDs. Celecoxib is metabolized primarily by CYP2C9 and may be increased or decreased by CYP2C9 modifiers such as fluconazole (200 mg once/day), fluvastatin, and zafirlukast. When, it was administered concomitantly with celecoxib, plasma level of coxib drug increased two folds (Garnett, 2001). It also inhibits CYP2D6 and may increase serum concentrations for a substantial number of agents that are substrates for CYP2D6, including many antidepressants (selective serotonin reuptake inhibitors, tricyclic antidepressants), antifungals, antipsychotics (flecainide, propafenone, haloperidol, etc.), analgesics such as codeine, and β-blockers (Werner et al., 2003). Significant interactions were reported for the administration of celecoxib with lithium. In fact, it decreases the clearance of lithium by inhibiting synthesis of renal prostaglandins, thereby elevating its plasma levels and lead to toxic effects (Gunja et al., 2002; Slørdal et al., 2003). Celecoxib showed an antagonistic drug-interaction with many anti-cancer drugs as doxorubicin (El-Awady et al., 2011) and platin derivative drugs such as cisplatin or oxaliplatin (Bijman et al., 2008; Chen et al., 2013; Kong et al., 2016).
Analgesic, Anti-Inflammatory, Antipyretic, and Anesthetic Drugs: Dealing With Pain, Inflammation, and Fever
Published in Richard J. Sundberg, The Chemical Century, 2017
The first COX-2 inhibitor to be introduced in the United States was celecoxib as Celebrex. It was discovered at Searle, which subsequently had been acquired by Pfizer. Celebrex was introduced in 1999 and had sales of $1.5 billion in its first year. The second COX-2 inhibitor to be introduced was rofecoxib (Vioxx) by Merck in 2000. It had $400 million in sales in its first year and $2.5 billion by 2003. The sales of both drugs were increased by vigorous direct consumer advertising based on the reduced gastrointestinal side effects. The introduction of these drugs was rapid by most standards, barely 10 years between discovery of COX-2 and the introduction of the drugs. A corollary of this rapid introduction was that the longest of the safety studies submitted for drug approval were less than 1 year in duration. For example, the assessment of the gastrointestinal effects was by endoscopic examination searching for abnormalities, rather than the more extended time that would be required for development of symptomatic conditions.
Aptamers: Scope, Limitations, and Future Prospects
Published in Rakesh N. Veedu, Aptamers, 2017
The author is currently working through an NIH SBIR grant (No. 2 R43 GM101712-01) on what may be a future commercial application of aptamers in the area of long-term pain relief for burn and cancer patients. Pain is often mediated by small molecules such as prostaglandins. NSAIDs inhibit the cyclooxygenase-2 (COX-2) enzyme so as to reduce prostaglandin production after tissue damage and thereby temporarily ameliorate pain. Similarly, the author is working with Professor Kenneth Hargreaves (Chair of Endodontics at the Univ. of Texas Health Science Center in San Antonio) who discovered that oxidized linoleic acid metabolites (OLAMs) known as hydroxyoctadecadienoic acids (HODES) mediate heat or burn pain and some types of cancer pain and shock [53, 93]. Hargreaves and Bruno recently patented (US Patent Application No. 14/029,440; Notice of Allowance granted Jan. 6, 2015) several aptamer DNA sequences having high affinity to 9-HODE and 13-HODE, respectively, as illustrated by the relative affinity ranking (darkest-green color) in a simple ELASA microplate assay from the author’s laboratory for one of the HODEs (Fig. 13.3). The anti-HODE aptamers inhibit electrical activity from excited isolated nerves in patch clamp experiments (Fig. 13.4) and when rats are injected in their hind limbs and held against a 43°C metal block, they do not recoil, suggesting strongly that they cannot feel the heat pain generated by the block.
Transdermal delivery of acemetacin loaded microemulsions: preparation, characterization, in vitro – ex vivo evaluation and in vivo analgesic and anti-inflammatory efficacy
Published in Journal of Dispersion Science and Technology, 2023
Emre Şefik Çağlar, Mehmet Evren Okur, Buket Aksu, Neslihan Üstündağ Okur
Due to the obvious importance of the cyclooxygenase (COX) pathway in inflammation and, hence, the biochemical identification of pain, nonsteroidal anti-inflammatory medications (NSAIDs), which include both conventional nonselective NSAIDs and selective COX-2 inhibitors, are widely used in pain management.[1] Acemetacin (ACM), the glycolic acid ester of indomethacin, is a nonselective COX-2 inhibitor. ACM, like other NSAIDs, is practically water-insoluble and inhibits prostaglandin production, resulting in an anti-inflammatory, analgesic, and antipyretic effect. Rheumatoid arthritis, osteoarthritis, low back pain, acute gout, dysmenorrhea, toothache, and postoperative pain are among the conditions for which it is prescribed. ACM is excreted via the hepatic and renal systems.[2,3]
Expression levels of selected cytokines and microRNAs in response to vitamin D supplementation in ultra-marathon runners
Published in European Journal of Sport Science, 2020
D. Pastuszak-Lewandoska, D. Domańska-Senderowska, J. Kiszałkiewicz, P. Szmigielska, A. Snochowska, W. Ratkowski, M. Spieszny, T. Klocek, P. Godlewski, P. Cięszczyk, E. Brzeziańska-Lasota, A. V. September, M. J. Laguette
COX-2 activity is stimulated by inflammation. This enzyme mediates the synthesis of prostaglandins involved in the inflammatory process. However, we did not find significant differences in COX-2 mRNA levels measured before and after the race: a decrease was observed after the race in the group with vitamin D supplementation, while in the group without supplementation its level was slightly increased. The inhibitory effect of vitamin D on COX-2 expression on mRNA and protein level is shown in several cancers, including prostate cancer cells (Moreno, Krishnan, Peehl, & Feldman, 2006). To the best of our knowledge, it is the first study analysing circulating COX-2 mRNA expression levels in UM runners. In most studies, COX-2 expression is increased after physical activity, although measured in muscle biopsies and most often at the protein level (Carroll et al., 2013; Weinheimer et al., 2007). None of the previous studies described the influence of vitamin D supplementation on its expression.
Biocompatibility of subcutaneously implanted marine macromolecules cross-linked bio-composite scaffold for cartilage tissue engineering applications
Published in Journal of Biomaterials Science, Polymer Edition, 2018
A. S. Sumayya, G. Muraleedhara Kurup
The inflammatory response related to anesthetized surgery and to trauma (accidental or unanesthetized injury) could be considered a surgical inflammation. In the immune phase of the inflammatory response, the interstitium is infiltrated first by platelets and later by leukocytes. Acute inflammation following surgery is the site for abundant production of ROS by phagocytic NADPH oxidase [46]. Natural biodegradable polymer scaffold can prevent the chronic inflammation, since it permits the scaffolds to retain their structural stability for a longer time after implantation [47]. COX and LOX are two significant enzymes which catalyze the formation of mediators involved in the inflammatory process. COX pathway converts arachidonic acid into the prostaglandins. Two types of cyclooxygenases (COX-1 and COX-2) have been identified as the key enzymes regulating the production of prostaglandins. COX-2 is an inducible enzyme whose expression is enhanced in response to inflammatory stimuli. LOX enzyme catalyzes the production of leukotrienes from arachidonic acid, which is also involved in the inflammatory process [48]. Nitric oxide (NO) is a signaling molecule that plays a key role in the pathogenesis of inflammation. It gives an anti-inflammatory effect under normal physiological conditions. On the other hand, NO is considered as a pro-inflammatory mediator that induces inflammation due to over production in abnormal situations [49]. NO is extensively produced by most of the cells of immune system such as dendritic cells, Natural Killer cells, mast cells and macrophages up on a pro-inflammatory stimulation. Among various isoforms of nitric oxide synthase, inducible nitric oxide synthase (iNOS) is responsible for the formation of NO in immune cells [50]. HACF containing chitosan and fucoidan plays a significant role in the control of acute and chronic inflammation via enzyme inhibition and inhibition of the complement cascade [51,52]. In the present study, activities of major inflammatory mediators such as COX, 5/15-LOX and NOS were found to be significantly increased in HACF and SMI implanted groups when compared to control after 1st week of implantation surgery. But after 4th and 8th week, their levels were found to be normal indicating decreased inflammatory response due to anti-inflammatory properties exerted by HACF scaffold (Figure 6A–C).